Alpha-and beta-amino acid hydroxyethylamino sulfonyl urea derivatives useful as retroviral protease inhibitors

ABSTRACT

α- and β-amino acid hydroxyethylamino sulfonyl urea derivative compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The present invention relates to retroviral protease inhibitorsand, more particularly, relates to novel compounds and a composition andmethod for inhibiting retroviral proteases. This invention, inparticular, relates to sulfonyl urea derivatives of hydroxyethylamineprotease inhibitor compounds, a composition and method for inhibitingretroviral proteases such as human immunodeficiency virus (HIV) proteaseand for treating a retroviral infection, e.g., an HIV infection. Thesubject invention also relates to processes for making such compounds aswell as to intermediates useful in such processes.

[0003] 2. Related Art

[0004] During the replication cycle of retroviruses, gag and gag-polgene products are translated as proteins. These proteins aresubsequently processed by a virally encoded protease (or proteinase) toyield viral enzymes and structural proteins of the virus core. Mostcommonly, the gag precursor proteins are processed into the coreproteins and the pol precursor proteins are processed into the viralenzymes, e.g., reverse transcriptase and retroviral protease. It hasbeen shown that correct processing of the precursor proteins by theretroviral protease is necessary for assembly of infectious virons. Forexample, it has been shown that frameshift mutations in the proteaseregion of the pol gene of HIV prevents processing of the gag precursorprotein. It has also been shown through site-directed mutagenesis of anaspartic acid residue in the HIV protease that processing of the gagprecursor protein is prevented. Thus, attempts have been made to inhibitviral replication by inhibiting the action of retroviral proteases.

[0005] Retroviral protease inhibition may involve a transition-statemimetic whereby the retroviral protease is exposed to a mimetic compoundwhich binds to the enzyme in competition with the gag and gag-polproteins to thereby inhibit replication of structural proteins and, moreimportantly, the retroviral protease itself. In this manner, retroviralreplication proteases can be effectively inhibited.

[0006] Several classes of compounds have been proposed, particularly forinhibition of proteases, such as for inhibition of HIV protease. Suchcompounds include hydroxyethylamine isosteres and reduced amideisosteres. See, for example, EP O 346 847; EP O 342,541; Roberts et al,“Rational Design of Peptide-Based Proteinase Inhibitors,” Science, 248,358 (1990); and Erickson et al, “Design Activity, and 2.8 Å CrystalStructure of a C₂ Symmetric Inhibitor Complexed to HIV-1 Protease,”Science, 249, 527 (1990).

[0007] Several classes of compounds are known to be useful as inhibitorsof the proteolytic enzyme renin. See, for example, U.S. Pat. No.4,599,198; U.K. 2,184,730; G.B. 2,209,752; EP O 264 795; G.B. 2,200,115and U.S. SIR H725. Of these, G.B. 2,200,115, GB 2,209,752, EP O 264,795,U.S. SIR H725 and U.S. Pat. No. 4,599,198 disclose urea-containinghydroxyethylamine renin inhibitors. G.B. 2,200,115 also disclosessulfamic acid-containing hydroxyethylamine renin inhibitors, and EP 0264795 discloses certain sulfamic acid-containing hydroxyethylamine renininhibitors. However, it is known that, although renin and HIV proteasesare both classified as aspartyl proteases, compounds which are effectiverenin inhibitors generally cannot be predicted to be effective HIVprotease inhibitors.

BRIEF DESCRIPTION OF THE INVENTION

[0008] The present invention is directed to virus inhibiting compoundsand compositions. More particularly, the present invention is directedto retroviral protease inhibiting compounds and compositions, to amethod of inhibiting retroviral proteases, to processes for preparingthe compounds and to intermediates useful in such processes. The subjectcompounds are characterized as derivatives of hydroxyethylamino sulfonylurea inhibitor compounds.

DETAILED DESCRIPTION OF THE INVENTION

[0009] In accordance with the present invention, there is provided aretroviral protease inhibiting compound of the formula:

[0010] or a pharmaceutically acceptable salt, prodrug or ester thereofwherein:

[0011] R represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,aralkyl, alkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl,aralkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl,cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl, aralkanoyl,aroyl, aryloxycarbonyl, aryloxycarbonylalkyl, aryloxyalkanoyl,heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylalkanoyl,heterocyclylalkoxycarbonyl, heteroaralkanoyl, heteroaralkoxycarbonyl,heteroaryloxycarbonyl, heteroaroyl, hydroxyalkyl, aminocarbonyl,aminoalkanoyl, and mono- and disubstituted aminocarbonyl and mono- anddisubstituted aminoalkanoyl radicals wherein the substituents areselected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkyalkylradicals, or wherein said aminocarbonyl and aminoalkanoyl radicals aredisubstituted, said substituents along with the nitrogen atom to whichthey are attached form a heterocycloalkyl or heteroaryl radical;

[0012] R′ represents hydrogen, radicals as defined for R³ or R″SO₂—wherein R″ represents radicals as defined for R³; or R and R′ togetherwith the nitrogen to which they are attached represent heterocycloalkyland heteroaryl radicals;

[0013] R¹ represents hydrogen, —CH₂SO₂NH₂, —CH₂CO₂CH₃, —CO₂CH₃, —CONH₂,—CH₂C(O)NHCH₃, —C(CH₃)₂(SH), —C(CH₃)₂(SCH₃), —C(CH₃)₂(S[O]CH₃),—C(CH₃)₂(S[O]₂CH₃), alkyl, haloalkyl, alkenyl, alkynyl and cycloalkylradicals, and amino acid side chains selected from asparagine, S-methylcysteine and methionine and the sulfoxide (SO) and sulfone (SO₂)derivatives thereof, isoleucine, allo-isoleucine, alanine, leucine,tert-leucine, phenylalanine, ornithine, histidine, norleucine,glutamine, threonine, glycine, allo-threonine, serine, O-alkyl serine,aspartic acid, beta-cyanoalanine and valine side chains;

[0014] R¹′ and R¹″ independently represent hydrogen and radicals asdefined for R¹, or one of R¹′ and R¹″, together with R¹ and the carbonatoms to which R¹, R¹′ and R¹″ are attached, represent a cycloalkylradical;

[0015] R² represents alkyl, aryl, cycloalkyl, cycloalkylalkyl andaralkyl radicals, which radicals are optionally substituted with a groupselected from alkyl and halogen radials, —NO₂, —CN, —CF₃, —OR⁹ and —SR⁹,wherein R⁹ represents hydrogen and alkyl radicals, and halogen radicals;

[0016] R³ represents alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl,heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl andmono- and disubstituted aminoalkyl radicals, wherein said substituentsare selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroaralkyl, heterocycloalkyl, and heterocycloalkylalkylradicals, or in the case of a disubstituted aminoalkyl radical, saidsubstituents along with the nitrogen atom to which they are attached,form a heterocycloalkyl or a heteroaryl radical, and thioalkyl,alkylthioalkyl and arylthioalkyl radicals or the sulfone or sulfoxidederivatives thereof;

[0017] R⁴ represents hydrogen and radicals as defined by R³;

[0018] R⁶ represents hydrogen and alkyl radicals;

[0019] R⁷ and R⁷′ independently represent hydrogen and radicals asdefined for R³; amino acid side chains selected from the groupconsisting of valine, isoleucine, glycine, alanine, allo-isoleucine,asparagine, leucine, glutamine, and t-butylglycine; radicals representedby the formulas —C(O)R¹⁶, —CO₂R¹⁶, —SO₂R¹⁶, —SR¹⁶, —CONR¹⁶R¹⁷, —CF₃ and—NR¹⁶R¹⁷; or R⁷ and R⁷′ together with the carbon atom to which they areattached form a cycloalkyl radical;

[0020] R⁸ represents cyano, hydroxyl, alkyl, alkoxy, cycloalkyl, aryl,aralkyl, heterocycloalkyl and heteroaryl radicals and radicalsrepresented by the formulas C(O)R¹⁶, CO₂R¹⁶, SO₂R¹⁶, SR¹⁶, CONR¹⁶R¹⁷,CF₃ and NR¹⁶R¹⁷;

[0021] wherein R¹⁶ and R¹⁷ independently represent hydrogen and radicalsas defined for R³, or R¹⁶ and R¹⁷ together with a nitrogen to which theyare attached in the formula NR¹⁶R¹⁷ represent heterocycloalkyl andheteroaryl radicals;

[0022] x represents 1 or 2;

[0023] n represents an integer of from 0 to 6;

[0024] t represents either 0, 1 or 2; and

[0025] Y represents O, S and NR¹⁵ wherein R¹⁵ represents hydrogen andradicals as defined for R³.

[0026] Examples of compounds of the present invention as defined byFormula I include:

[0027] 1)2S-[[(dimethylamino)acetyl]amino]-N-[3-[[[(2-hydroxy-1,1-dimethylethyl)amino]sulfonyl](3-methylbutyl)amino]-2R-hydroxy-1S-(phenylmethyl)propyl]-3,3-dimethylbutanamide

[0028] 2)N-[[[3S-[[2S-[[(dimethylamino)acetyl]amino]-3,3-dimethyl-1-oxobutyl]amino]-2R-hydroxy-4-phenylbutyl](3-methylbutyl)amino]sulfonyl]-2-methylalanine

[0029] 3)N-[[[3S-[[2S-[[(dimethylamino)acetyl]amino]-3,3-dimethyl-1-oxobutyl]amino]-2R-hydroxy-4-phenylbutyl](3-methylbutyl)amino]sulfonyl]-2-methylalanine,methyl ester

[0030] 4)1-[[[[3S-[[2S-[[(dimethylamino)acetyl]amino]-3,3-dimethyl-1-oxobutyl]amino]-2R-hydroxy-4-phenylbutyl](4-pyridinylmethyl)amino]sulfonyl]amino]cyclopentanecarboxylicacid

[0031] 5)N-[[[3S-[[4-amino-1,4-dioxo-2S-[(2-quinolinylcarbonyl)amino]butyl]amino]-2R-hydroxy-4-phenylbutyl](2-methylpropyl))amino]sulfonyl]-2-methylalanine

[0032] 6)3-[[[[3S-[[2R-[[(dimethylamino)acetyl]amino]-3-methyl-3-(methylthio)-1-oxobutyl]amino]-2R-hydroxy-4-phenylbutyl](2-methylpropyl)amino]sulfonyl]amino]-3-methylbutanoicacid

[0033] 7)N-[[[2R-hydroxy-3S-[[3-[[[(4-methoxyphenyl)methoxy]carbonyl]amino]-2R-methyl-1-oxopropyl]amino]-4-phenylbutyl(3-methylbutyl)amino]sulfonyl]-2-methylalanine

[0034] 8)3-[[[[3S-[[2S-[[(dimethylamino)acetyl]amino]-3-methyl-1-oxopentyl]amino]-2R-hydroxy-4-phenylbutyl][(4-fluorophenyl)methyl]amino]sulfonyl]amino]-2-methylpropanoicacid

[0035] 9)1-[[[[2R-hydroxy-3S-[[3-methyl-1-oxo-2S-[[(phenylmethoxy)carbonyl]amino]butyl]amino]-4-phenylbutyl](3-methylbutyl)amino]sulfonyl]amino]cyclopentanecarboxylicacid

[0036] 10)1-[[[3S-[[4-amino-1,4-dioxo-2S-[(2-quinolinylcarbonyl)amino]butyl]amino]-2R-hydroxy-4-phenylbutyl](3-methylbutyl)amino]sulfonyl]amino]cyclopropanecarboxylicacid

[0037] A family of compounds of particular interest within Formula I arecompounds embraced by Formula II:

[0038] wherein:

[0039] R represents hydrogen, alkyl, alkenyl, cycloalkyl, hydroxyalkyl,aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl, alkoxycarbonyl,alkoxyalkyl, aralkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl,cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl, aralkanoyl,aroyl, aryloxycarbonyl, aryloxycarbonylalkyl, aryloxyalkanoyl,heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylalkanoyl,heterocyclylalkoxycarbonyl, heteroaralkanoyl, heteroaralkoxycarbonyl,heteroaryloxy-carbonyl, heteroaroyl, aminocarbonyl, aminoalkanoyl, andmono- and disubstituted aminocarbonyl and mono- and disubstitutedaminoalkanoyl radicals wherein the substituents are selected from alkyl,aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl,heterocycloalkyl, heterocycloalkyalkyl radicals, or where saidaminoalkanoyl radical is disubstituted, said substituents along with thenitrogen atom to which they are attached form a heterocycloalkyl orheteroaryl radical;

[0040] R′ represents hydrogen and radicals as defined for R³ or R and R′together with the nitrogen to which they are attached representheterocycloalkyl and heteroaryl radical;

[0041] R¹ represents hydrogen, —CH₂SO₂NH₂, —CH₂CO₂CH₃, —CO₂CH₃, —CONH₂,—CH₂C(O)NHCH₃, —C(CH₃)₂(SH), —C(CH₃)₂(SCH₃), —C(CH₃)₂(S[O]CH₃),—C(CH₃)₂(S[O]₂CH₃), alkyl, haloalkyl, alkenyl, alkynyl and cycloalkylradicals, and amino acid side chains selected from asparagine, S-methylcysteine and methionine and the sulfoxide (SO) and sulfone (SO₂)derivatives thereof, isoleucine, allo-isoleucine, alanine, leucine,tert-leucine, phenylalanine, ornithine, histidine, norleucine,glutamine, threonine, glycine, allo-threonine, serine, O-methyl serine,aspartic acid, beta-cyanoalanine and valine side chains;

[0042] R² represents alkyl, aryl, cycloalkyl, cycloalkylalkyl andaralkyl radicals, which radicals are optionally substituted with a groupselected from alkyl and halogen radials, —NO₂, —C≡N, CF₃, —OR⁹, —SR⁹,wherein R⁹ represents hydrogen and alkyl radicals;

[0043] R³ represents alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl,heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl andmono- and disubstituted aminoalkyl radicals, wherein said substituentsare selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroaralkyl, heterocycloalkyl, and heterocycloalkylalkylradicals, or in the case of a disubstituted aminoalkyl radical, saidsubstituents along with the nitrogen atom to which they are attached,form a heterocycloalkyl or a heteroaryl radical, and thioalkyl,alkylthioalkyl and arylthioalkyl radicals and the sulfone or sulfoxidederivatives thereof;

[0044] R⁴ represents hydrogen and radicals as defined by R³;

[0045] R⁷ and R⁷′ independently represent radicals as defined for R³;amino acid side chains selected from the group consisting of valine,isoleucine, glycine, alanine, allo-isoleucine, asparagine, leucine,glutamine, and t-butylglycine; radicals represented by the formulas—C(O)R¹⁶, —CO₂R¹⁶, —SO₂R¹⁶, —SR¹⁶, —CONR¹⁶R¹⁷, —CF₃ and —NR¹⁶R¹⁷; or R⁷and R⁷′ together with the carbon atom to which they are attached form acycloalkyl radical;

[0046] R⁸ represents cyano, hydroxyl, alkyl, alkoxy, cycloalkyl, aryl,aralkyl, heterocycloalkyl and heteroaryl radicals and radicalsrepresented by the formulas C(O)R¹⁶, CO₂R¹⁶, SO₂R¹⁶, SR¹⁶, CONR¹⁶R¹⁷,CF₃ and NR¹⁶R¹⁷;

[0047] wherein R¹⁶ and R¹⁷ independently represent hydrogen and radicalsas defined for R³, or R¹⁶ and R¹⁷ together with a nitrogen to which theyare attached in the formula NR¹⁶R¹⁷ represent heterocycloalkyl andheteroaryl radicals;

[0048] n represents an integer of from 0 to 6;

[0049] A more preferred family of compounds within Formula II consistsof compounds wherein:

[0050] R represents hydrogen, alkyl, alkenyl, cycloalkyl, aryl, aralkyl,alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl,cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl, aralkanoyl,aroyl, aryloxycarbonyl, aryloxycarbonylalkyl, aryloxyalkanoyl,heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylalkanoyl,heterocyclylalkoxycarbonyl, heteroaralkanoyl, heteroaralkoxycarbonyl,heteroaryloxycarbonyl, heteroaroyl, aryloxyalkyl, heteroaryloxyalkyl,hydroxyalkyl, aminocarbonyl, aminoalkanoyl, and mono- and disubstitutedaminocarbonyl and mono- and disubstituted aminoalkanoyl radicals whereinthe substituents are selected from alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl,heterocycloalkyalkyl radicals, or where said aminoalkanoyl radical isdisubstituted, said substituents along with the nitrogen atom to whichthey are attached form a heterocycloalkyl or heteroaryl radical;

[0051] R′ represents hydrogen and radicals as defined for R³ or R and R′together with the nitrogen to which they are attached representheterocycloalkyl and heteroaryl radical;

[0052] R¹ represents CH₂C(O)NHCH₃, C(CH₃)₂(SCH₃), C(CH₃)₂(S[O]CH₃),C(CH₃)₂(S[O]₂CH₃), alkyl, alkenyl and alkynyl radicals, and amino acidside chains selected from the group consisting of asparagine, valine,threonine, allo-threonine, isoleucine, tert-leucine, S-methyl cysteineand methionine and the sulfone and sulfoxide derivatives thereof,alanine, and allo-isoleucine;

[0053] R² represents alkyl, cycloalkylalkyl and aralkyl radicals, whichradicals are optionally substituted with halogen radicals and radicalsrepresented by the formula —OR⁹ and —SR⁹ wherein R⁹ represents alkylradicals; and

[0054] R³ represents alkyl, haloalkyl, alkenyl, alkoxyalkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyland heteroaralkyl radicals;

[0055] R⁴ represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl,heteroaryl, aralkyl, heteroaralkyl, heterocycloalkyl andheterocycloalkylalkyl radicals;

[0056] R⁷ and R⁷′ independently represent alkyl and aralkyl radicals ortogether with the carbon atom to which they are attached form acycloalkyl radical having from 3 to 8 carbon atoms;

[0057] R⁸ represents alkylcarbonyl, aryl, aroyl, aryloxy, aralkanoyl,cyano, hydroxycarbonyl, arylsulfonyl, alkylsulfonyl, alkylthio,hydroxyl, alkoxy, heteroaryl, dialkylaminocarbonyl, dialkylamino,cycloalkylamino, heterocyclylamino and alkoxycarbonyl radicals; and

[0058] n is an integer of from 0 to 6;

[0059] Of highest interest are compounds within Formula II wherein

[0060] R represents alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl,cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl,alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl,aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl,heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroaralkanoyl,heteroaralkoxycarbonyl, heteroaryloxy-carbonyl, heteroaroyl,aminocarbonyl, aminoalkanoyl, and mono- and disubstituted aminocarbonyland mono- and disubstituted aminoalkanoyl radicals wherein thesubstituents are selected from alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl,heterocycloalkyalkyl radicals, or where said aminoalkanoyl radical isdisubstituted, said substituents along with the nitrogen atom to whichthey are attached form a heterocycloalkyl or heteroaryl radical;

[0061] R′ represents hydrogen and radicals as defined for R³ or R and R′together with the nitrogen to which they are attached representheterocycloalkyl and heteroaryl radical;

[0062] R¹ represents CH₂C(O)NHCH₃, C(CH₃)₂(SCH₃), C(CH₃)₂(S[O]CH₃),C(CH₃)₂(S[O]₂CH₃), methyl, propargyl, t-butyl, isopropyl and sec-butylradicals, and amino acid side chains selected from the group consistingof asparagine, valine, S-methyl cysteine, allo-iso-leucine, iso-leucine,and beta-cyano alanine side chains;

[0063] R² represents CH₃SCH₂CH₂—, iso-butyl, n-butyl, benzyl,4-fluorobenzyl, 2-naphthylmethyl and cyclohexylmethyl radicals;

[0064] R³ represents propyl, isoamyl, n-butyl, isobutyl, cyclohexyl,cyclohexylmethyl, benzyl and pyridylmethyl radicals;

[0065] R⁴ represents hydrogen and methyl, ethyl, i-propyl, propyl,n-butyl, t-butyl, 1,1-dimethylpropyl, cyclohexyl and phenyl radicals;

[0066] R⁷ and R⁷′ independently represent methyl, ethyl, propyl andbutyl radicals, or together with the carbon atom to which they areattached form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexylradical;

[0067] R⁸ represents methylcarbonyl, phenyl, hydroxy, methoxy, cyano,methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, t-butoxycarbonyl,benzyloxycarbonyl, carboxyl, methoxycarbonyl, methylsulfonyl,methylthio, phenylsulfonyl, phenyl, 2-, 3- or 4-pyridyl, 2-, 3- or4-pyridyl N-oxide, N,N-dimethylamino, 1-piperidinyl, 4-morpholinyl,4-(N-methyl)piperazinyl and 1-pyrrolidinyl.

[0068] Another family of compounds of particular interest within FormulaI are compounds embraced by Formula III:

[0069] wherein:

[0070] R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl,alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl,cycloalkylalkanoyl, alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl,aryloxycarbonylalkyl, aryloxyalkanoyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, heterocyclylalkanoyl,heterocyclylalkoxycarbonyl, heteroaralkanoyl, heteroaralkoxycarbonyl,heteroaryloxy-carbonyl, heteroaroyl, alkyl, alkenyl, cycloalkyl, aryl,aralkyl, aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, hydroxyalkyl,aminocarbonyl, aminoalkanoyl, and mono- and disubstituted aminocarbonyland mono- and disubstituted aminoalkanoyl radicals wherein thesubstituents are selected from alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl,heterocycloalkyalkyl radicals, or where said aminoalkanoyl radical isdisubstituted, said substituents along with the nitrogen atom to whichthey are attached form a heterocycloalkyl or heteroaryl radical;

[0071] R′ represents hydrogen and radicals as defined for R³ or R and R′together with the nitrogen to which they are attached representheterocycloalkyl and heteroaryl radical;

[0072] R¹ represents hydrogen, —CH₂SO₂NH₂, —CH₂CO₂CH₃, —CO₂CH₃, —CONH₂,—CH₂C(O)NHCH₃, —C(CH₃)₂(SH), —C(CH₃)₂(SCH₃), —C(CH₃)₂(S[O]CH₃),—C(CH₃)₂(S[O]₂CH₃), alkyl, haloalkyl, alkenyl, alkynyl and cycloalkylradicals, and amino acid side chains selected from asparagine, S-methylcysteine and the sulfoxide (SO) and sulfone (SO₂) derivatives thereof,isoleucine, allo-isoleucine, alanine, leucine, tert-leucine,phenylalanine, ornithine, histidine, norleucine, glutamine, threonine,glycine, allo-threonine, serine, aspartic acid, beta-cyano alanine andvaline side chains;

[0073] R¹′ and R¹″ independently represent hydrogen and radicals asdefined for R¹, or one of R¹′ and R¹″, together with R¹ and the carbonatoms to which R¹, R¹′ and R¹″ are attached, represent a cycloalkylradical;

[0074] R² represents alkyl, aryl, cycloalkyl, cycloalkylalkyl andaralkyl radicals, which radicals are optionally substituted with a groupselected from alkyl and halogen radials, —NO₂, —C≡N, CF₃, —OR⁹ and —SR⁹,wherein R⁹ represents hydrogen and alkyl radicals;

[0075] R³ represents alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl,heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl andmono- and disubstituted aminoalkyl radicals, wherein said substituentsare selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroaralkyl, heterocycloalkyl, and heterocycloalkylalkylradicals, or in the case of a disubstituted aminoalkyl radical, saidsubstituents along with the nitrogen atom to which they are attached,form a heterocycloalkyl or a heteroaryl radical, and thioalkyl,alkylthioalkyl and arylthioalkyl radicals and the sulfone or sulfoxidederivatives thereof;

[0076] R⁴ represents hydrogen and radicals as defined by R³;

[0077] R⁷ and R⁷′ independently represent radicals as defined for R³;amino acid side chains selected from the group consisting of valine,isoleucine, glycine, alanine, allo-isoleucine, asparagine, leucine,glutamine, and t-butylglycine; radicals represented by the formulas—C(O)R¹⁶, —CO₂R¹⁶, —SO₂R¹⁶, —SR¹⁶, —CONR¹⁶R¹⁷, —CF₃ and —NR¹⁶R¹⁷; or R⁷and R⁷′ together with the carbon atom to which they are attached form acycloalkyl radical;

[0078] R⁸ represents cyano, hydroxyl, alkyl, alkoxy, cycloalkyl, aryl,aralkyl, heterocycloalkyl and heteroaryl radicals and radicalsrepresented by the formulas C(O)R¹⁶, CO₂R¹⁶, SO₂R¹⁶, SR¹⁶, CONR¹⁶R¹⁷,CF₃ and NR¹⁶R¹⁷;

[0079] wherein R¹⁶ and R¹⁷ independently represent hydrogen and radicalsas defined for R³, or R¹⁶ and R¹⁷ together with a nitrogen to which theyare attached in the formula NR¹⁶R¹⁷ represent heterocycloalkyl andheteroaryl radicals;

[0080] n represents an integer of from 0 to 6;

[0081] A more preferred family of compounds within Formula III consistsof compounds wherein

[0082] R represents an arylalkanoyl, heteroaroyl, aryloxyalkanoyl,aryloxycarbonyl, alkanoyl, aminocarbonyl, mono-substitutedaminoalkanoyl, or disubstituted aminoalkanoyl, or mono- ordialkylaminocarbonyl radical;

[0083] R′ represents hydrogen and radicals as defined for R³ or R and R′together with the nitrogen to which they are attached represent aheterocycloalkyl or heteroaryl radical;

[0084] R¹, R¹′ and R¹″ independently represent hydrogen and alkylradicals having from 1 to about 4 carbon atoms, alkenyl, alkynyl,aralkyl radicals, and radicals represented by the formula —CH₂C(O)R″ or—C(O)R″ wherein R″ represents R³⁸, —NR³⁸R³⁹ and OR³⁸ wherein R³⁸ and R³⁹independently represent hydrogen and alkyl radicals having from 1 toabout 4 carbon atoms;

[0085] R² represents alkyl, cycloalkylalkyl and aralkyl radicals, whichradicals are optionally substituted with halogen radicals and radicalsrepresented by the formula —OR⁹ and —SR⁹ wherein R⁹ represents hydrogenand alkyl radicals; and

[0086] R³ represents alkyl, haloalkyl, alkenyl, alkynyl, alkoxyalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,aryl, aralkyl, heteroaryl and heteroaralkyl radicals;

[0087] R⁴ represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl,heteroaryl, aralkyl, heteroaralkyl, heterocycloalkyl andheterocycloalkylalkyl radicals, or R⁴ and R⁵ together with the nitrogenatom to which they are bonded from a heterocycloalkyl or heteroarylradical;

[0088] R⁷ and R⁷′ independently represent alkyl and aralkyl radicals ortogether with the carbon atom to which they are attached form acycloalkyl radical having from 3 to 8 carbon atoms;

[0089] R⁸ represents alkylcarbonyl, aryl, aroyl, aryloxy, aralkanoyl,cyano, hydroxycarbonyl, arylsulfonyl, alkylsulfonyl, alkylthio,hydroxyl, alkoxy, heteroaryl, dialkylaminocarbonyl, dialkylamino,cycloalkylamino, heterocyclylamino and alkoxycarbonyl radicals.

[0090] Of highest interest are compounds of Formula III wherein:

[0091] R represents an arylalkanoyl, aryloxycarbonyl, heteroaroyl,aryloxyalkanoyl, alkanoyl, aminocarbonyl, mono-substitutedaminoalkanoyl, or disubstituted aminoalkanoyl, or mono- ordialkylaminocarbonyl radical;

[0092] R′ represents hydrogen and radicals as defined for R³ or R and R′together with the nitrogen to which they are attached represent aheterocycloalkyl or heteroaryl radical;

[0093] R¹, R¹′ and R¹″ independently represent hydrogen, methyl, ethyl,benzyl, phenylpropyl, —C(O)NH₂ and propargyl radicals;

[0094] R² represents CH₃SCH₂CH₂—, iso-butyl, n-butyl, benzyl,4-fluorobenzyl, 2-naphthylmethyl and cyclohexylmethyl radicals;

[0095] R³ represents propyl, isobutyl, isoamyl, n-butyl, n-propyl,cyclohexyl, cyclohexylmethyl, benzyl and pyridylmethyl radicals;

[0096] R⁴ represents hydrogen and methyl, ethyl, i-propyl, n-butyl,t-butyl, 1,1-dimethylpropyl, cyclohexyl and phenyl radicals;

[0097] R⁷ and R⁷′ independently represent methyl, ethyl, propyl andbutyl radicals, or together with the carbon atom to which they areattached form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexylradical;

[0098] R⁸ represents methylcarbonyl, phenyl, hydroxy, methoxy, cyano,methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, t-butoxycarbonyl,benzyloxycarbonyl, carboxyl, methoxycarbonyl, methylsulfonyl,methylthio, phenylsulfonyl, phenyl, 2-, 3- or 4-pyridyl, 2-, 3- or4-pyridyl N-oxide, N,N-dimethylamino, 1-piperidinyl, 4-morpholinyl,4-(N-methyl)piperazinyl and 1-pyrrolidinyl.

[0099] Another family of compounds of particular interest within FormulaI are compounds embraced by Formula IV:

[0100] wherein:

[0101] R represents hydrogen, alkyl, alkenyl, cycloalkyl, aryl, aralkyl,aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl, alkoxycarbonyl,aralkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl,cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl, aralkanoyl,aroyl, aryloxycarbonyl, aryloxycarbonylalkyl, alkoxyalkyl,aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl,heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroaralkanoyl,heteroaralkoxycarbonyl, heteroaryloxy-carbonyl, heteroaroyl,aminocarbonyl, aminoalkanoyl, and mono- and disubstituted aminocarbonyland mono- and disubstituted aminoalkanoyl radicals wherein thesubstituents are selected from alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl,heterocycloalkyalkyl radicals, or where said aminoalkanoyl radical isdisubstituted, said substituents along with the nitrogen atom to whichthey are attached form a heterocycloalkyl or heteroaryl radical;

[0102] R′ represents hydrogen and radicals as defined for R³ or R and R′together with the nitrogen to which they are attached representheterocycloalkyl and heteroaryl radical;

[0103] R¹ represents hydrogen, —CH₂SO₂NH₂, —CH₂CO₂CH₃, —CO₂CH₃, —CONH₂,—CH₂C(O)NHCH₃, —C(CH₃)₂(SH), —C(CH₃)₂(SCH₃), —C(CH₃)₂(S[O]CH₃),—C(CH₃)₂(S[O]₂CH₃), alkyl, haloalkyl, alkenyl, alkynyl and cycloalkylradicals, and amino acid side chains selected from asparagine, S-methylcysteine and methionine and the sulfoxide (SO) and sulfone (SO₂)derivatives thereof, isoleucine, allo-isoleucine, alanine, leucine,tert-leucine, phenylalanine, ornithine, histidine, norleucine,glutamine, threonine, glycine, allo-threonine, serine, aspartic acid,beta-cyano alanine and valine side chains;

[0104] R² represents alkyl, aryl, cycloalkyl, cycloalkylalkyl andaralkyl radicals, which radicals are optionally substituted with a groupselected from alkyl and halogen radicals, —NO₂, —C≡N, CF₃, —OR⁹, —SR⁹,wherein R⁹ represents hydrogen and alkyl;

[0105] R³ represents alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl,heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl andmono- and disubstituted aminoalkyl radicals, wherein said substituentsare selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroaralkyl, heterocycloalkyl, and heterocycloalkylalkylradicals, or in the case of a disubstituted aminoalkyl radical, saidsubstituents along with the nitrogen atom to which they are attached,form a heterocycloalkyl or a heteroaryl radical, and thioalkyl,alkylthioalkyl and arylthioalkyl radicals and the sulfone or sulfoxidederivatives thereof;

[0106] R⁴ represents hydrogen and radicals as defined for R³;

[0107] R⁷ and R⁷′ independently represent radicals as defined for R³;amino acid side chains selected from the group consisting of valine,isoleucine, glycine, alanine, allo-isoleucine, asparagine, leucine,glutamine, and t-butylglycine; radicals represented by the formulas—C(O)R¹⁶, —CO₂R¹⁶, —SO₂R¹⁶, —SR¹⁶, —CONR¹⁶R¹⁷, —CF₃ and —NR¹⁶R¹⁷; or R⁷and R⁷′ together with the carbon atom to which they are attached form acycloalkyl radical;

[0108] R⁸ represents cyano, hydroxyl, alkyl, alkoxy, cycloalkyl, aryl,aralkyl, heterocycloalkyl and heteroaryl radicals and radicalsrepresented by the formulas C(O)R¹⁶, CO₂R¹⁶, SO₂R¹⁶, SR¹⁶, CONR¹⁶R¹⁷,CF₃ and NR¹⁶R¹⁷;

[0109] wherein R¹⁶ and R¹⁷ independently represent hydrogen and radicalsas defined for R³, or R¹⁶ and R¹⁷ together with a nitrogen to which theyare attached in the formula NR¹⁶R¹⁷ represent heterocycloalkyl andheteroaryl radicals;

[0110] n represents an integer of from 0 to 6.

[0111] A more preferred family of compounds within Formula IV consistsof compounds wherein

[0112] R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl,alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl,cycloalkylalkanoyl, alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl,aryloxycarbonylalkyl, aryloxyalkanoyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, heterocyclylalkanoyl,heterocyclylalkoxycarbonyl, heteroaralkanoyl, heteroaralkoxycarbonyl,heteroaryloxy-carbonyl, heteroaroyl, alkyl, alkenyl, cycloalkyl, aryl,aralkyl, aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl, aminocarbonyl,aminoalkanoyl, and mono- and disubstituted aminocarbonyl and mono- anddisubstituted aminoalkanoyl radicals wherein the substituents areselected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkyalkylradicals, or where said aminoalkanoyl radical is disubstituted, saidsubstituents along with the nitrogen atom to which they are attachedform a heterocycloalkyl or heteroaryl radical;

[0113] R′ represents hydrogen and radicals as defined for R³ or R and R′together with the nitrogen to which they are attached representheterocycloalkyl and heteroaryl radical;

[0114] R¹ represents hydrogen, alkyl, alkenyl, and alkynyl radicals, andamino acid side chains selected from the group consisting of asparagine,valine, threonine, allo-threonine, isoleucine, tert-leucine, S-methylcysteine and the sulfone and sulfoxide derivatives thereof, alanine, andallo-isoleucine;

[0115] R² represents alkyl, cycloalkylalkyl and aralkyl radicals, whichradicals are optionally substituted with halogen radicals and radicalsrepresented by the formula —OR⁹ and —SR⁹ wherein R⁹ represents hydrogenand alkyl and halogen radicals;

[0116] R³ represents alkyl, haloalkyl, alkenyl, alkoxyalkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl,heteroaryl and heteroaralkyl radicals;

[0117] R⁴ represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl,heteroaryl, aralkyl, heteroaralkyl, heterocycloalkyl andheterocycloalkylalkyl radicals;

[0118] R⁷ and R⁷′ independently represent alkyl and aralkyl radicals ortogether with the carbon atom to which they are attached form acycloalkyl radical having from 3 to 8 carbon atoms;

[0119] R⁸ represents alkylcarbonyl, aryl, aroyl, aryloxy, aralkanoyl,cyano, hydroxycarbonyl, arylsulfonyl, alkylsulfonyl, alkylthio,hydroxyl, alkoxy, heteroaryl, dialkylaminocarbonyl, dialkylamino,cycloalkylamino, heterocyclylamino and alkoxycarbonyl radicals; and

[0120] n represents an integer of from 0 to 6.

[0121] Of highest interest are compounds within Formula IV wherein

[0122] R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl,alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl,cycloalkylalkanoyl, alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl,aryloxycarbonylalkyl, aryloxyalkanoyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, heterocyclylalkanoyl,heterocyclylalkoxycarbonyl, heteroaralkanoyl, heteroaralkoxycarbonyl,heteroaryloxy-carbonyl, heteroaroyl, aminocarbonyl, aminoalkanoyl, andmono- and disubstituted aminocarbonyl and mono- and disubstitutedaminoalkanoyl radicals wherein the substituents are selected from alkyl,aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl,heterocycloalkyl, heterocycloalkyalkyl radicals, or where saidaminoalkanoyl radical is disubstituted, said substituents along with thenitrogen atom to which they are attached form a heterocycloalkyl orheteroaryl radical;

[0123] R′ represents hydrogen and radicals as defined for R³ or R and R′together with the nitrogen to which they are attached representheterocycloalkyl and heteroaryl radical;

[0124] R¹ represents hydrogen, methyl, propargyl, t-butyl, isopropyl andsec-butyl radicals, and amino acid side chains selected from the groupconsisting of asparagine, valine, S-methyl cysteine, allo-iso-leucine,iso-leucine, threonine, serine, aspartic acid, beta-cyano alanine, andallo-threonine side chains;

[0125] R² represents CH₃SCH₂CH₂—, iso-butyl, n-butyl, benzyl,4-fluorobenzyl, 2-naphthylmethyl and cyclohexylmethyl radicals;

[0126] R³ represents propyl, isobutyl, isoamyl, n-butyl, cyclohexyl,cyclohexylmethyl, benzyl and pyridylmethyl radicals;

[0127] R⁴ represents hydrogen and methyl, ethyl, i-propyl, n-propyl,n-butyl, t-butyl, 1,1-dimethylpropyl, cyclohexyl and phenyl radicals;

[0128] R⁷ and R⁷′ independently represent methyl, ethyl, propyl andbutyl radicals, or together with the carbon atom to which they areattached form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexylradical;

[0129] R⁸ represents methylcarbonyl, phenyl, hydroxy, methoxy, cyano,methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, t-butoxycarbonyl,benzyloxycarbonyl, carboxyl, methoxycarbonyl, methylsulfonyl,methylthio, phenylsulfonyl, phenyl, 2-, 3- or 4-pyridyl, 2-, 3- or4-pyridyl N-oxide, N,N-dimethylamino, 1-piperidinyl, 4-morpholinyl,4-(N-methyl)piperazinyl and 1-pyrrolidinyl; and

[0130] n represents an integer of from 0 to 6.

[0131] As utilized herein, the term “alkyl”, alone or in combination,means a straight-chain or branched-chain alkyl radical containing from 1to about 10, preferably from 1 to 8, carbon atoms. Examples of suchradicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like. Theterm “alkenyl”, alone or in combination, means a straight-chain orbranched-chain hydrocarbon radial having one or more double bonds andcontaining from 2 to about 18 carbon atoms preferably from 2 to 8 carbonatoms. Examples of suitable alkenyl radicals include ethenyl, propenyl,1,4-butadienyl, 12-octadecene and the like. The term “alkynyl”, alone orin combination, means a straight-chain hydrocarbon radical having one ormore triple bonds and containing from 2 to about 10 carbon atoms,preferably from 2 to 8 carbon atoms. Examples of alkynyl radicalsinclude ethynyl, propynyl, (propargyl), butynyl and the like. The term“alkoxy”, alone or in combination, means an alkyl ether radical whereinthe term alkyl is as defined above. Examples of suitable alkyl etherradicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,iso-butoxy, sec-butoxy, tert-butoxy and the like. The term “cycloalkyl”,alone or in combination, means a saturated or partially saturatedmonocyclic, bicyclic or tricyclic alkyl radical wherein each cyclicmoiety contains from about 3 to about 8 carbon atoms and is cyclic. Theterm “cycloalkylalkyl” means an alkyl radical as defined above which issubstituted by a cycloalkyl radical containing from about 3 to about 8,preferably from 3 to 6 carbon atoms. Examples of such cycloalkylradicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andthe like. The term “aryl”, alone or in combination, means a phenyl ornaphthyl radical which optionally carries one or more substituentsselected from alkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano,haloalkyl and the like, such as phenyl, p-tolyl, 4-methoxyphenyl,4-(tert-butoxy)phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-hydroxyphenyl,1-naphthyl, 2-naphthyl, and the like. The term “aralkyl”, alone or incombination, means an alkyl radical as defined above in which onehydrogen atom is replaced by an aryl radical as defined above, such asbenzyl, 2-phenylethyl and the like. The term “aralkoxy carbonyl”, aloneor in combination, means a radical of the formula —C(O)—O-aralkyl inwhich the term “aralkyl” has the significance given above. An example ofan aralkoxycarbonyl radical is benzyloxycarbonyl. The term “aryloxy”means a radical of the formula aryl-O— in which the term aryl has thesignificance given above. The term “alkanoyl”, alone or in combination,means an acyl radical derived from an alkanecarboxylic acid whereinalkane means a radical as defined above for alkyl. Examples of alkanoylradicals include acetyl, propionyl, butyryl, valeryl, 4-methylvaleryl,and the like. The term “cycloalkylcarbonyl” means an acyl group derivedfrom a monocyclic or bridged cycloalkanecarboxylic acid such ascyclopropanecarbonyl, cyclohexanecarbonyl, adamantanecarbonyl, and thelike, or from a benz-fused monocyclic cycloalkanecarboxylic acid whichis optionally substituted by, for example, alkanoylamino, such as1,2,3,4-tetrahydro-2-naphthoyl,2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl. The term “aralkanoyl” meansan acyl radical derived from an aryl-substituted alkanecarboxylic acidsuch as phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl),4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl,4-aminohydrocinnamoyl, 4-methoxyhydrocinnamoyl, and the like. The term“aroyl” means an acyl radical derived from an aromatic carboxylic acid.Examples of such radicals include aromatic carboxylic acids, anoptionally substituted benzoic or naphthoic acid such as benzoyl,4-chlorobenzoyl, 4-carboxybenzoyl, 4-(benzyloxycarbonyl)benzoyl,1-naphthoyl, 2-naphthoyl, 6-carboxy-2 naphthoyl,6-(benzyloxycarbonyl)-2-naphthoyl, 3-benzyloxy-2-naphthoyl,3-hydroxy-2-naphthoyl, 3-(benzyloxyformamido)-2-naphthoyl, and the like.The heterocyclyl or heterocycloalkyl portion of a heterocyclylcarbonyl,heterocyclyloxycarbonyl, heterocyclylalkoxycarbonyl, or heterocyclyalkylgroup or the like is a saturated or partially unsaturated monocyclic,bicyclic or tricyclic heterocycle which contains one or more heteroatoms selected from nitrogen, oxygen and sulphur, which is optionallysubstituted on one or more carbon atoms by halogen, alkyl, alkoxy, oxo,and the like, and/or on a secondary nitrogen atom (i.e., —NH—) by alkyl,aralkoxycarbonyl, alkanoyl, phenyl or phenylalkyl or on a tertiarynitrogen atom (i.e. ═N—) by oxido and which is attached via a carbonatom. The heteroaryl portion of a heteroaroyl, heteroaryloxycarbonyl, ora heteroaralkoxy carbonyl group or the like is an aromatic monocyclic,bicyclic, or tricyclic heterocycle which contains the hetero atoms andis optionally substituted as defined above with respect to thedefinition of heterocyclyl. Such heterocyclyl and heteroaryl radicalshave from four to about 12 ring members, preferably from 4 to 10 ringmembers. Examples of such heterocyclyl and heteroaryl groups arepyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl,pyrrolyl, imidazolyl (e.g., imidazol 4-yl,1-benzyloxycarbonylimidazol-4-yl, etc.), pyrazolyl, pyridyl, pyrazinyl,pyrimidinyl, furyl, thienyl, triazolyl, oxazolyl, thiazolyl, indolyl(e.g., 2-indolyl, etc.), quinolinyl, (e.g., 2-quinolinyl, 3-quinolinyl,1-oxido-2-quinolinyl, etc.), isoquinolinyl (e.g., 1-isoquinolinyl,3-isoquinolinyl, etc.), tetrahydroquinolinyl (e.g.,1,2,3,4-tetrahydro-2-quinolyl, etc.), 1,2,3,4-tetrahydroisoquinolinyl(e.g., 1,2,3,4-tetrahydro-1-oxo-isoquinolinyl, etc.), quinoxalinyl,β-carbolinyl, 2-benzofurancarbonyl, 1-, 2-, 4- or 5-benzimidazolyl, andthe like. The term “cycloalkylalkoxycarbonyl” means an acyl groupderived from a cycloalkylalkoxycarboxylic acid of the formulacycloalkylalkyl-O—COOH wherein cycloalkylalkyl has the significancegiven above. The term “aryloxyalkanoyl” means an acyl radical of theformula aryl-O-alkanoyl wherein aryl and alkanoyl have the significancegiven above. The term “heterocyclyloxycarbonyl” means an acyl groupderived from heterocyclyl-O—COOH wherein heterocyclyl is as definedabove. The term “heterocyclylalkanoyl” is an acyl radical derived from aheterocyclyl-substituted alkane carboxylic acid wherein heterocyclyl hasthe significance given above. The term “heterocyclylalkoxycarbonyl”means an acyl radical derived from a heterocyclyl-substitutedalkane-O—COOH wherein heterocyclyl has the significance given above. Theterm “heteroaryloxycarbonyl” means an acyl radical derived from acarboxylic acid represented by heteroaryl-O—COOH wherein heteroaryl hasthe significance given above. The term “aminocarbonyl” alone or incombination, means an amino-substituted carbonyl (carbamoyl) groupderived from an amino-substituted carboxylic acid wherein the aminogroup can be a primary, secondary or tertiary amino group containingsubstituents selected from hydrogen, and alkyl, aryl, aralkyl,cycloalkyl, cycloalkylalkyl radicals and the like. The term“aminoalkanoyl” means an acyl group derived from an amino-substitutedalkanecarboxylic acid wherein the amino group can be a primary,secondary or tertiary amino group containing substituents selected fromhydrogen, and alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicalsand the like. The term “halogen” means fluorine, chlorine, bromine oriodine. The term “haloalkyl” means an alkyl radical having thesignificance as defined above wherein one or more hydrogens are replacedwith a halogen. Examples of such haloalkyl radicals includechloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl,trifluoromethyl, 1,1,1-trifluoroethyl and the like. The term “leavinggroup” generally refers to groups readily displaceable by a nucleophile,such as an amine, a thiol or an alcohol nucleophile. Such leaving groupsare well known in the art. Examples of such leaving groups include, butare not limited to, N-hydroxysuccinimide, N-hydroxybenzotriazole,halides, triflates, tosylates and the like. Preferred leaving groups areindicated herein where appropriate.

[0132] Procedures for preparing the compounds of Formula I are set forthbelow. It should be noted that the general procedure is shown as itrelates to preparation of compounds having the specifiedstereochemistry, for example, wherein the absolute stereochemistry aboutthe hydroxyl group is designated as (R), which is the preferredstereochemistry for the compounds of the present invention. However,such procedures are generally applicable to those compounds of oppositeconfiguration, e.g., where the stereochemistry about the hydroxyl groupis (S). In addition, the compounds having the (R) stereochemistry can beutilized to produce those having the (S) stereochemistry. For example, acompound having the (R) stereochemistry can be inverted to the (S)stereochemistry using well-known methods.

Preparation of Compounds of Formula I

[0133] The compounds of the present invention represented by Formula Iabove can be prepared utilizing the following general procedure. Thisprocedure is schematically shown in the following Schemes I-V:

[0134] An N-protected chloroketone derivative of an amino acid havingthe formula:

[0135] wherein P represents an amino protecting group, and R² is asdefined above, is reduced to the corresponding alcohol utilizing anappropriate reducing agent. Suitable amino protecting groups are wellknown in the art and include carbobenzoxy, t-butoxycarbonyl, and thelike. A preferred amino protecting group is carbobenzoxy. A preferredN-protected chloroketone is N-benzyloxycarbonyl-L-phenylalaninechloromethyl ketone. A preferred reducing agent is sodium borohydride.The reduction reaction is conducted at a temperature of from −10° C. toabout 25° C., preferably at about 0° C., in a suitable solvent systemsuch as, for example, tetrahydrofuran, and the like. The N-protectedchloroketones are commercially available, e.g., such as from Bachem,Inc., Torrance, Calif. Alternatively, the chloroketones can be preparedby the procedure set forth in S. J. Fittkau, J. Prakt. Chem., 315, 1037(1973), and subsequently N-protected utilizing procedures which are wellknown in the art.

[0136] The halo alcohol can be utilized directly, as described below,or, preferably, is then reacted, preferably at room temperature, with asuitable base in a suitable solvent system to produce an N-protectedamino epoxide of the formula:

[0137] wherein P and R² are as defined above. Suitable solvent systemsfor preparing the amino epoxide include ethanol, methanol, isopropanol,tetrahydrofuran, dioxane, and the like including mixtures thereof.Suitable bases for producing the epoxide from the reduced chloroketoneinclude potassium hydroxide, sodium hydroxide, potassium t-butoxide, DBUand the like. A preferred base is potassium hydroxide.

[0138] Alternatively, a protected amino epoxide can be prepared startingwith an L-amino acid which is reacted with a suitable amino-protectinggroup in a suitable solvent to produce an amino-protected L-amino acidester of the formula:

[0139] wherein P¹ and P² independently represent hydrogen, benzyl andamino-protecting groups (as defined above), provided that P¹ and P² arenot both hydrogen; P³ represents carboxyl-protecting group, e.g.,methyl, ethyl, benzyl, tertiary-butyl and the like; and R² is as definedabove.

[0140] The amino-protected L-amino acid ester is then reduced, to thecorresponding alcohol. For example, the amino-protected L-amino acidester can be reduced with diisobutylaluminum hydride at −78° C. in asuitable solvent such as toluene. The resulting alcohol is thenconverted, for example, by way of a Swern oxidation, to thecorresponding aldehyde of the formula:

[0141] wherein P¹, P² and R² are as defined above. Thus, adichloromethane solution of the alcohol is added to a cooled (−75 to−68° C.) solution of oxalyl chloride in dichloromethane and DMSO indichloromethane and stirred for 35 minutes.

[0142] The aldehyde resulting from the Swern oxidation is then reactedwith a halomethyllithium reagent, which reagent is generated in situ byreacting an alkyllithium or arylithium compound with a dihalomethanerepresented by the formula X¹CH₂X² wherein X¹ and X² independentlyrepresent I, Br or Cl. For example, a solution of the aldehyde andchloroiodomethane in THF is cooled to −78° C. and a solution ofn-butyllithium in hexane is added. The resulting product is a mixture ofdiastereomers of the corresponding amino-protected epoxides of theformulas:

[0143] The diastereomers can be separated e.g., by chromatography, or,alternatively, once reacted in subsequent steps the diastereomericproducts can be separated. For compounds having the (S) stereochemistry,a D-amino acid can be utilized in place of the L-amino acid.

[0144] The amino epoxide is then reacted, in a suitable solvent system,with an equal amount, or preferably an excess of, a desired amine of theformula:

R³NH₂

[0145] wherein R³ is hydrogen or is as defined above. The reaction canbe conducted over a wide range of temperatures, e.g., from about 10° C.to about 100° C., but is preferably, but not necessarily, conducted at atemperature at which the solvent begins to reflux. Suitable solventsystems include protic, non-protic and dipolar aprotic organic solventssuch as, for example, those wherein the solvent is an alcohol, such asmethanol, ethanol, isopropanol, and the like, ethers such astetrahydrofuran, dioxane and the like, and toluene,N,N-dimethylformamide, dimethyl sulfoxide, and mixtures thereof. Apreferred solvent is isopropanol. Exemplary amines corresponding to theformula R³NH₂ include benzyl amine, isobutylamine, n-butyl amine,isopentyl amine, isoamylamine, cyclohexanemethyl amine, naphthylenemethyl amine and the like. The resulting product is a 3-(N-protectedamino)-3-(R²)-1-(NHR³)-propan-2-ol derivative (hereinafter referred toas an amino alcohol) can be represented by the formulas:

[0146] wherein P, P¹, P², R² and R³ are as described above.Alternatively, a haloalcohol can be utilized in place of the aminoepoxide.

[0147] The amino alcohol defined above is then reacted in a suitablesolvent with a sulfamoyl halide, e.g. sulfamoyl chloride[R⁸(CH₂)_(n)C(R⁷R⁷′)][R⁴]NSO₂Cl or sulfamoyl anhydride in the presenceof an acid scavenger. Suitable solvents in which the reaction can beconducted include methylene chloride, tetrahydrofuran. Suitable acidscavengers include triethylamine, pyridine. The resulting sulfamic acidderivative can be represented, depending on the epoxide utilized, by theformulas;

[0148] wherein P, P¹, P², R², R³, R⁴, R⁵, R⁷, R⁷′, R⁸ and n are asdefined above. These intermediates are useful for preparing inhibitorcompounds of the present invention and are also active inhibitors ofretroviral proteases.

[0149] The sulfamoyl halides of the formula[R⁸(CH₂)_(n)C(R⁷R⁷′)][R⁴]NSO₂X, wherein R⁴ is hydrogen can be preparedby the reaction of a suitable isocyanate of the formula[R⁸(CH₂)_(n)C(R⁷R⁷′)][R⁴]NCO with fuming sulfuric acid to produce thecorresponding sulfamate which is then converted to the halide by wellknown procedures, such as by treating the sulfamate with PCl₅.Alternatively the isocyanate can be treated with chlorosulfonic acid toproduce the corresponding sulfamoyl chloride directly.

[0150] The sulfamoyl halides of the formula[R⁸(CH₂)_(n)C(R⁷R⁷′)][R⁴]NSO₂Cl, wherein R⁴ is other than hydrogen, canbe prepared by reacting an amine of the formula[R⁸(CH₂)_(n)C(R⁷R⁷′)][R⁴]NH, preferably as a salt such as thehydrochloride, with sulfuryl chloride in a suitable solvent such asacetonitrile. The reaction mixture is gradually warmed to refluxtemperature and maintained at the reflux temperature until the reactionis complete. Alternatively, sulfamoyl halides of the formula[R⁸(CH₂)_(n)C(R⁷R⁷′)][R⁴]NSO₂Cl can be prepared by reacting an amine ofthe fomula [R⁸(CH₂)_(n)C(R⁷R⁷′)][R⁴]NH with sulfuryl chloride in boilingMeCN as disclosed in Matier et al., J. Med. Chem., 15, No. 5, p.538(1972).

[0151] Alternatively, the sulfamoyl halide can be prepared by reacting asulfamoyl halide derivative of an isocyanate, i.e., a derivative of theformula ClSO₂NCO with an appropriate alcohol of the formulaHOC(R⁷R⁷′)(CH₂)_(n)R⁸ to produce the corresponding compound of theformula ClSO₂NHC(O)OC(R⁷R⁷′)(CH₂)_(n)R⁸. Following deletion of thecarbonyl moiety a sulfamoyl halide of the formulaClSO₂NHC(R⁷R⁷′)(CH₂)_(n)R⁸ is produced. This procedure is described inJ. Org. Chem., 54, 5826-5828 (1989). Alternatively, the amino alcoholcan be reacted with a chlorosulfonyl methyl ester of the formula ClSO₂Oalkyl to produce the corresponding derivative and then reacted with anamine of the formula HNR⁴R⁵.

[0152] Following preparation of the sulfonyl urea derivative, the aminoprotecting group P or P¹ and P² amino protecting groups are removedunder conditions which will not affect the remaining portion of themolecule. These methods are well known in the art and include acidhydrolysis, hydrogenolysis and the like. A preferred method involvesremoval of the protecting group, e.g., removal of a carbobenzoxy group,by hydrogenolysis utilizing palladium on carbon in a suitable solventsystem such as an alcohol, acetic acid, and the like or mixturesthereof. Where the protecting group is a t-butoxycarbonyl group, it canbe removed utilizing an inorganic or organic acid, e.g., HCl ortrifluoroacetic acid, in a suitable solvent system, e.g., dioxane ormethylene chloride. The resulting product is the amine salt derivative.Following neutralization of the salt, the amine is then reacted with anamino acid or corresponding derivative thereof represented by theformula (PN[CR¹′R¹″]_(t)CH(R¹)COOH) wherein t, R¹, R¹′ and R¹″ are asdefined above, to produce the antiviral compounds of the presentinvention having the formula:

[0153] wherein t, P, R¹, R¹′, R¹″, R², R³, R⁴, R⁵, R⁷, R⁷′, R⁸ and n areas defined above. Preferred protecting groups in this instance are abenzyloxycarbonyl group or a t-butoxycarbonyl group. Where the amine isreacted with a derivative of an amino acid, e.g., when t=1 and R¹′ andR¹″ are both H, so that the amino acid is a β-amino acid, such β-aminoacids can be prepared according to the procedure set forth in acopending application, U.S. Ser. No. 07/345,808. Where t is 1, one ofR¹′ and R¹″ is H and R¹ is hydrogen so that the amino acid is ahomo-β-amino acid, such homo-β-amino acids can be prepared by theprocedure set forth in a copending application, U.S. Ser. No.07/853,561. Where t is O and R¹ is alkyl, alkenyl, alkynyl, cycloalkyl,—CH₂SO₂NH₂, —CH₂CO₂CH₃, —CO₂CH₃, —CONH₂, —CH₂C(O)NHCH₃, —C(CH₃)₂(SH),—C(CH₃)₂(SCH₃), —C(CH₃)₂[S(O)CH₃], —C(CH₃)₂[S(O₂)CH₃], or an amino acidside chain, such materials are well known and many are commerciallyavailable from Sigma-Aldrich.

[0154] The N-protecting group can be subsequently removed, if desired,utilizing the procedures described above, and then reacted with acarboxylate represented by the formula:

[0155] wherein R is as defined above and L is an appropriate leavinggroup such as a halide. Preferably, where R¹ is a side chain of anaturally occurring α-amino acid, R is a 2-quinoline carbonyl groupderived from N-hydroxysuccinimide-2-quinoline carboxylate, i.e., L ishydroxy succinimide. A solution of the free amine (or amine acetatesalt) and about 1.0 equivalent of the carboxylate are mixed in anappropriate solvent system and optionally treated with up to fiveequivalents of a base such as, for example, N-methylmorpholine, at aboutroom temperature. Appropriate solvent systems include tetrahydrofuran,methylene chloride or N,N-dimethylformamide, and the like, includingmixtures thereof.

[0156] Alternatively, the protected amino alcohol from the epoxideopening can be further protected at the newly introduced amino groupwith a protecting group P′ which is not removed when the firstprotecting P is removed. One skilled in the art can choose appropriatecombinations of P and P′. One suitable choice is when P is Cbz and P′ isBoc. The resulting compound represented by the formula:

[0157] can be carried through the remainder of the synthesis to providea compound of the formula:

[0158] and the new protecting group P′ is selectively removed, andfollowing deprotection, the resulting amine reacted to form the sulfamicacid derivative as described above. This selective deprotection andconversion to the sulfonyl urea derivative can be accomplished at eitherthe end of the synthesis or at any appropriate intermediate step ifdesired.

[0159] It is contemplated that for preparing compounds of the Formulashaving R⁶, the compounds can be prepared following the procedure setforth above and, prior to coupling the sulfonamide derivative or analogthereof, e.g. coupling to the amino acid PNH(CH₂)_(t)CH(R¹)COOH, carriedthrough a procedure referred to in the art as reductive amination. Thus,a sodium cyanoborohydride and an appropriate aldehyde or ketone can bereacted with the sulfonamide derivative compound or appropriate analogat room temperature in order to reductively aminate any of the compoundsof Formulas I-IV. It is also contemplated that where R³ of the aminoalcohol intermediate is hydrogen, the inhibitor compounds of the presentinvention wherein R³ is alkyl, or other substituents wherein the α-Ccontains at least one hydrogen, can be prepared through reductiveamination of the final product of the reaction between the amino alcoholand the amine or at any other stage of the synthesis for preparing theinhibitor compounds.

[0160] Contemplated equivalents of the general formulas set forth abovefor the antiviral compounds and derivatives as well as the intermediatesare compounds otherwise corresponding thereto and having the samegeneral properties, such as tautomers thereof as well as compounds,wherein one or more of the various R groups are simple variations of thesubstituents as defined therein, e.g., wherein R is a higher alkyl groupthan that indicated. In addition, where a substituent is designated as,or can be, a hydrogen, the exact chemical nature of a substituent whichis other than hydrogen at that position, e.g., a hydrocarbyl radical ora halogen, hydroxy, amino and the like functional group, is not criticalso long as it does not adversely affect the overall activity and/orsynthesis procedure.

[0161] The chemical reactions described above are generally disclosed interms of their broadest application to the preparation of the compoundsof this invention. Occasionally, the reactions may not be applicable asdescribed to each compound included within the disclosed scope. Thecompounds for which this occurs will be readily recognized by thoseskilled in the art. In all such cases, either the reactions can besuccessfully performed by conventional modifications known to thoseskilled in the art, e.g., by appropriate protection of interferinggroups, by changing to alternative conventional reagents, by routinemodification of reaction conditions, and the like, or other reactionsdisclosed herein or otherwise conventional, will be applicable to thepreparation of the corresponding compounds of this invention. In allpreparative methods, all starting materials are known or readilypreparable from known starting materials.

[0162] Without further elaboration, it is believed that one skilled inthe art can, using the preceding description, utilize the presentinvention to its fullest extent. The following preferred specificembodiments are, therefore, to be construed as merely illustrative, andnot limitative of the remainder of the disclosure in any way whatsoever.

[0163] All reagents were used as received without purification. Allproton and carbon NMR spectra were obtained on either a Varian VXR-300or VXR-400 nuclear magnetic resonance spectrometer.

[0164] The following Examples 1 through 9 illustrate preparation ofintermediates. These intermediates are useful in preparing the inhibitorcompounds of the present invention as illustrated in Examples 13-17. Inaddition, the intermediates of Examples 4-9 are also retroviral proteaseinhibitors and inhibit, in particular, HIV protease.

EXAMPLE 1

[0165]

Preparation ofN[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenylbutyl]-N-isoamylamine

[0166] Part A:

[0167] To a solution of 75.0 g (0.226 mol) ofN-benzyloxycarbonyl-L-phenylalanine chloromethyl ketone in a mixture of807 mL of methanol and 807 mL of tetrahydrofuran at −2° C., was added13.17 g (0.348 mol, 1.54 equiv.) of solid sodium borohydride over onehundred minutes. The solvents were removed under reduced pressure at 40°C. and the residue dissolved in ethyl acetate (approx. 1 L). Thesolution was washed sequentially with 1M potassium hydrogen sulfate,saturated sodium bicarbonate and then saturated sodium chloridesolutions. After drying over anhydrous magnesium sulfate and filtering,the solution was removed under reduced pressure. To the resulting oilwas added hexane (approx. 1 L) and the mixture warmed to 60° C. withswirling. After cooling to room temperature, the solids were collectedand washed with 2 L of hexane. The resulting solid was recrystallizedfrom hot ethyl acetate and hexane to afford 32.3 g (43% yield) ofN-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol, mp150-151° C. and M+Li⁺=340.

[0168] Part B:

[0169] To a solution of 6.52 g (0.116 mol, 1.2 equiv.) of potassiumhydroxide in 968 mL of absolute ethanol at room temperature, was added32.3 g (0.097 mol) of N-CBZ-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol.After stirring for fifteen minutes, the solvent was removed underreduced pressure and the solids dissolved in methylene chloride. Afterwashing with water, drying over magnesium sulfate, filtering andstripping, one obtains 27.9 g of a white solid. Recrystallization fromhot ethyl acetate and hexane afforded 22.3 g (77% yield) ofN-benzyloxycarbonyl-3(S)-amino-1,2(S)-epoxy-4-phenylbutane, mp 102-103°C. and MH⁺ 298.

[0170] Part C:

[0171] A solution of N-benzyloxycarbonyl3(S)-amino-1,2-(S)-epoxy-4-phenylbutane (1.00 g, 3.36 mmol) andisoamylamine (4.90 g, 67.2 mmol, 20 equiv.) in 10 mL of isopropylalcohol was heated to reflux for 1.5 hours. The solution was cooled toroom temperature, concentrated in vacuo and then poured into 100 mL ofstirring hexane whereupon the product crystallized from solution. Theproduct was isolated by filtration and air dried to give 1.18 g, 95% ofN=[[3(S)-phenylmethylcarbamoyl)amino-2(R)-hydroxy-4-phenylbutyl]N-[(3-methylbutyl)]aminemp 108.0-109.5° C., MH⁺ m/z=371.

EXAMPLE 2

[0172]

Preparation of N,N-dibenzyl-3(S)-amino-1,2-(S)-epoxy-4-phenylbutane

[0173] Step A:

[0174] A solution of L-phenylalanine (50.0 g, 0.302 mol), sodiumhydroxide (24.2 g, 0.605 mol) and potassium carbonate (83.6 g, 0.605mol) in water (500 ml) is heated to 97° C. Benzyl bromide (108.5 ml,0.912 mol) is then slowly added (addition time ˜25 min). The mixture isthen stirred at 97° C. for 30 minutes. The solution is cooled to roomtemperature and extracted with toluene (2×250 ml). The combined organiclayers are then washed with water, brine, dried over magnesium sulfate,filtered and concentrated to give an oil product. The crude product isthen used in the next step without purification.

[0175] Step B:

[0176] The crude benzylated product of the above step is dissolved intoluene (750 ml) and cooled to −55° C. A 1.5 M solution of DIBAL-H intoluene (443.9 ml, 0.666 mol) is then added at a rate to maintain thetemperature between −55° to −50° C. (addition time—1 hour). The mixtureis stirred for 20 minutes at −55° C. The reaction is quenched at −55° C.by the slow addition of methanol (37 ml). The cold solution is thenpoured into cold (5° C.) 1.5 N HCl solution (1.8 L). The precipitatedsolid (approx. 138 g) is filtered off and washed with toluene. The solidmaterial is suspended in a mixture of toluene (400 ml) and water (100ml). The mixture is cooled to 5° C., treated with 2.5 N NaOH (186 ml)and then stirred at room temperature until the solid is dissolved. Thetoluene layer is separated from the aqueous phase and washed with waterand brine, dried over magnesium sulfate, filtered and concentrated to avolume of 75 ml (89 g). Ethyl acetate (25 ml) and hexane (25 ml) arethen added to the residue upon which the alcohol product begins tocrystallize. After 30 min., an additional 50 ml hexane is added topromote further crystallization. The solid is filtered off and washedwith 50 ml hexane to give approximately 35 g of material. A second cropof matrial can be isolated by refiltering the mother liquor. The solidsare combined and recrystallized from ethyl acetate (20 ml) and hexane(30 ml) to give, in 2 crops, approximately 40 g (40% fromL-phenylalanine) of analytically pure alcohol product. The motherliquors are combined and concentrated (34 g). The residue is treatedwith ethyl acetate and hexane which provides an additional 7 g (˜7%yield) of slightly impure solid product. Further optimization in therecovery from the mother liquor is probable.

[0177] Step C:

[0178] A solution of oxalyl chloride (8.4 ml, 0.096 mol) indichloromethane (240 ml) is cooled to −74° C. A solution of DMSO (12.0ml, 0.155 mol) in dichloromethane (50 ml) is then slowly added at a rateto maintain the temperature at −74° C. (addition time ˜1.25 hr). Themixture is stirred for 5 min. followed by addition of a solution of thealcohol (0.074 mol) in 100 ml of dichloromethane (addition time—20 min.,temp. −75° C. to −68° C.). The solution is stirred at −78° C. for 35minutes. Triethylamine (41.2 ml, 0.295 mol) is then added over 10 min.(temp. −78° to −68° C.) upon which the ammonium salt precipitated. Thecold mixture is stirred for 30 min. and then water (225 ml) is added.The dichloromethane layer is separated from the aqueous phase and washedwith water, brine, dried over magnesium sulfate, filtered andconcentrated. The residue is diluted with ethyl acetate and hexane andthen filtered to further remove the ammonium salt. The filtrate isconcentrated to give the desired aldehyde product. The aldehyde wascarried on to the next step without purification.

[0179] Temperatures higher than −70° C. have been reported in theliterature for the Swern oxidation. Other Swern modifications andalternatives to the Swern oxidations are also possible.

[0180] A solution of the crude aldehyde 0.074 mol and chloroiodomethane(7.0 ml, 0.096 mol) in tetrahydrofuran (285 ml) is cooled to −78° C. A1.6 M solution of n-butyllithium in hexane (25 ml, 0.040 mol) is thenadded at a rate to maintain the temperature at −75° C. (addition time—15min.). After the first addition, additional chloroiodomethane (1.6 ml,0.022 mol) is added again, followed by n-butyllithium (23 ml, 0.037mol), keeping the temperature at −75° C. The mixture is stirred for 15min. Each of the reagents, chloroiodomethane (0.70 ml, 0.010 mol) andn-butyllithium (5 ml, 0.008 mol) are added 4 more times over 45 min. at−75° C. The cooling bath is then removed and the solution warmed to 22°C. over 1.5 hr. The mixture is poured into 300 ml of saturated aq.ammonium chloride solution. The tetrahydrofuran layer is separated. Theaqueous phase is extracted with ethyl acetate (1×300 ml). The combinedorganic layers are washed with brine, dried over magnesium sulfate,filtered and concentrated to give a brown oil (27.4 g). The productcould be used in the next step without purification. The desireddiastereomer can be purified by recrystallization at a subsequent step.

[0181] Alternately, the product could be purified by chromatography.

EXAMPLE 3

[0182]

Preparation of N[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenyl]N-isobutylamine

[0183] A solution ofN-benzyloxycarbonyl-3(S)-amino-1,2-(S)-epoxy-4-phenyl butane (50.0 g,0.168 mol) and isobutylamine (246 g, 3.24 mol, 20 equivalents) in 650 mLof isopropyl alcohol was heated to reflux for 1.25 hours. The solutionwas cooled to room temperature, concentrated in vacuo and then pouredinto 1 L of stirring hexane whereupon the product crystallized fromsolution. The product was isolated by filtration and air dried to give57.56 g, 92% ofN[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenyl]N-isobutylamine, mp108.0-109.5° C., MH+ m/z=371.

EXAMPLE 4 Preparation of Sulfamoyl Chlorides

[0184] Method A:

[0185] An amino acid ester hydrochloride (1 mmol) is suspended in asuitable solvent such as hexane, dichloromethane, toluene and the like,but most preferable acetonitrile. To the well stirred mixture is addedsulfuryl chloride (3 mmol) in a suitable solvent, or neat, dropwise overseveral minutes. The reaction is allowed to stir at zero to refluxtemperatures, preferable at reflux, for 1 to 48 hours, preferably for 24hours. The solvent is removed and the residue triturated with a suitablesolvent, such as hexane, pentane, toluene, but most preferably diethylether. The solvent is decanted and concentrated. The product may then beutilized as such or purified by distillation or in the case of solidsrecrystallized from appropriate solvents.

[0186] Method B:

[0187] An alpha-hydroxy ester (1 mmol) is dissolved in an appropriatesolvent such as acetonitrile, dichloromethane, toluene and the like, butmost preferable hexane. Chlorosulfonyl isocyanate (1 mmol) added neat orin a solvent, preferably in hexane, is added dropwise. The reaction isstirred from zero to reflux, preferably at reflux, for 5 minutes toseveral hours, preferably for 1 hour. The solvent is then removed andthe residue used as such, or taken up in an appropriate solvent,expecially dichloromethane, and filtered to remove any impurities. Theproduct may then be purified by distillation or in the case of solidsrecrystallized from appropriate solvents.

EXAMPLE 5 Preparation of Sulfamates

[0188] An amino alcohol as prepared in Example 3 (1 mmol) and a suitablebase, such as triethylamine, pyridine, sodium carbonate, and the like,preferably diisopropylethylamine (1 mmol) are dissolved in a suitablesolvent such as ether, chloroform, acetronitrile and the like, butpreferably dichloromethane. The sulfamoyl chloride from part A or B ofExample 4, neat or dissolved in an appropriate solvent, is added to theabove solution. The reaction is stirred at zero to reflux temperatures,but preferably at room temperature for 1 to 48 hours. The product can bepurified by silica gel chromatography or by an extractive workupfollowed by recrystallization.

[0189] The following Examples 6-8 illustrate preparation of β-amino acidintermediates. These intermediates can be coupled to the intermediatecompounds illustrated by those of Examples 4 and 5 to produce inhibitorcompounds of the present invention containing β-amino acids.

EXAMPLE 6 A. Preparation of 4(4-methoxybenzyl)itaconate

[0190]

[0191] A 5 L three-necked round bottomed flask equipped with constantpressure addition funnel, reflux condenser, nitrogen inlet, andmechanical stirrer was charged with itaconic anhydride (660.8 g, 5.88mol) and toluene (2300 mL). The solution was warmed to reflux andtreated with 4-methoxybenzyl alcohol (812.4 g, 5.88 mol) dropwise over a2.6 h period. The solution was maintained at reflux for an additional1.5 h and then the contents were poured into three 2 L erlenmeyer flasksto crystallize. The solution was allowed to cool to room temperaturewhereupon the desired mono-ester crystallized. The product was isolatedby filtration on a Buchner funnel and air dried to give 850.2 g, 58% ofmaterial with mp 83-85° C., a second crop, 17% was isolated aftercooling of the filtrate in an ice bath. ¹H NMR (CDCl₃) 300 MHz 7.32(d,J=8.7 Hz, 2H), 6.91(d, J=8.7 Hz, 2H), 6.49(s, 1H), 5.85(s, 1H), 5.12(s,2H), 3.83(s, 3H), 3.40(s, 2H).

B. Preparation of Methyl 4(4-methoxybenzyl) itaconate

[0192]

[0193] A 5 L three-necked round bottomed flask equipped with refluxcondenser, nitrogen inlet, constant pressure addition funnel andmechanical stirrer was charged with 4(4-methoxybenzyl) itaconate (453.4g, 1.81 mol) and treated with 1,5-diazabicyclo[4.3.0]non-5-ene (275.6 g,1.81 mol), (DBN), dropwise so that the temperature did not rise above15° C. To this stirring mixture was added a solution of methyl iodide(256.9 g, 1.81 mol) in 250 mL of toluene from the dropping funnel over a45 m period. The solution was allowed to warm to room temperature andstirred for an additional 3.25 h.

[0194] The precipitated DBN hydroiodide was removed by filtration,washed with toluene and the filtrate poured into a separatory funnel.The solution was washed with sat. aq. NaHCO₃ (2×500 mL), 0.2N HCl (1×500mL), and brine (2×500 mL), dried over anhyd. MgSO₄, filtered, and thesolvent removed in vacuo. This gave a clear colorless oil, 450.2 g, 94%whose NMR was consistent with the assigned structure. ¹H NMR (CDCl₃) 300MHz 7.30(d, J=8.7 Hz, 2H), 6.90(d, J=8.7 Hz, 2H), 6.34(s, 1H), 5.71(s,1H), 5.09(s, 2H), 3.82(s, 3H), 3.73(s, 3H), 3.38(s, 2H). ¹³C NMR (CDCl₃)170.46, 166.47, 159.51, 133.55, 129.97, 128.45, 127.72, 113.77, 66.36,55.12, 51.94, 37.64.

C. Preparation of Methyl 4(4-methoxybenzyl) 2(R)-methylsuccinate

[0195]

[0196] A 500 mL Fisher-Porter bottle was charged with methyl4(4-methoxybenzyl) itaconate (71.1 g, 0.269 mol), rhodium (R,R) DiPAMPcatalyst (204 mg, 0.269 mmol, 0.1 mol %) and degassed methanol (215 mL).The bottle was flushed 5 times with nitrogen and 5 times with hydrogento a final pressure of 40 psig. The hydrogenation commenced immediatelyand after ca. 1 h the uptake began to taper off, after 3 h the hydrogenuptake ceased and the bottle was flushed with nitrogen, opened and thecontents concentrated on a rotary evaporator to give a brown oil thatwas taken up in boiling iso-octane (ca. 200 mL, this was repeatedtwice), filtered through a pad of celite and the filtrate concentratedin vacuo to give 66.6 g, 93% of a clear colorless oil, ¹H NMR (CDCl₃ 300MHz 7.30(d, J=8.7 Hz, 2H), 6.91(d, J=8.7 Hz, 2H), 5.08(s, 2H), 3.82(s,3H), 3.67(s, 3H), 2.95(ddq, J=5.7, 7.5, 8.7 Hz, 1H), 2.79(dd, J=8.1,16.5 Hz, 1H), 2.45(dd, J=5.7, 16.5 Hz, 1H), 1.23(d, J=7.5 Hz, 3H).

D. Preparation of Methyl 2(R)-methylsuccinate

[0197] A 3 L three-necked round-bottomed flask equipped with a nitrogeninlet, mechanical stirrer, reflux condenser and constant pressureaddition funnel was charged with methyl 4(4-methoxybenzyl)2(R)-methylsuccinate (432.6 g, 1.65 mol) and toluene (1200 mL). Thestirrer was started and the solution treated with trifluoroacetic acid(600 mL) from the dropping funnel over 0.25 h. The solution turned adeep purple color and the internal temperature rose to 45° C. Afterstirring for 2.25 h the temperature was 27° C. and the solution hadacquired a pink color. The solution was concentrated on a rotaryevaporator. The residue was diluted with water (2200 mL) and sat. aq.NaHCO₃ (1000 mL). Additional NaHCO₃ was added until the acid had beenneutralized. The aqueous phase was extracted with ethyl acetate (2×1000mL) to remove the by-product

nd the aqueous layer was acidified to pH=1.8 with conc. HC

. This so

was extracted with ethyl acetate (4×

L), w

with brine, dried over anhyd. MgSO₄, filtered and concentrated on arotary evaporator to give a colorless liquid 251 g, >100% that wasvacuum distilled through a short path apparatus cut 1: bath temperature120° C. @ >1 mm, bp 25-29° C.; cut 2: bath temperature 140° C. @ 0.5 mm,bp 95-108° C., 151 g, [α]_(d) @ 25° C.=+1.38° C. (c=15.475, MeOH),[α]_(d)=+8.48° C. (neat); cut 3: bath temperature 140° C., bp 108° C.,36 g, [α]_(d) @ 25° C.=+1.49° C. (c=15.00, MeOH), [α]_(d)=+8.98° C.(neat). Cuts 2 and 3 were combined to give 189 g, 78% of product, ¹H NMR(CDCl₃) 300 MHz 11.6(brs, 1H), 3.72(s, 3H), 2.92(ddq, J=5.7, 6.9, 8.0Hz, 1H), 2.81(dd, J=8.0, 16.8 Hz, 1H), 2.47(dd, J=5.7, 16.8 Hz, 1H),1.26(d, J=6.9 Hz, 3H).

E. Preparation of Methyl Itaconate

[0198]

[0199] A 50 mL round bottomed flask equipped with reflux condenser,nitrogen inlet and magnetic stir bar was charged with methyl4(4-methoxybenzyl) itaconate (4.00 g, 16 mmol), 12 mL of touluene and 6mL of trifluoroacetic acid. The solution was kept at room temperaturefor 18 hours and then the volatiles were removed in vacuo. The residuewas taken up in ethyl acetate and extracted three times with saturatedaqueous sodium bicarbonate solution. The combined aqueous extract wasacidified to pH=1 with aqueous potassium bisulfate and then extractedthree times with ethyl acetate. The combined ethyl acetate solution waswashed with saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate, filtered, and concentrated in vacuo. The residue wasthen vacuum distilled to give 1.23 g, 75% of pure product, bp 85-87 @0.1 mm. ¹H NMR (CDCl₃) 300 MHz 6.34(s, 1H), 5.73(s, 2H), 3.76(s, 3H),3.38(s, 2H). ¹³C NMR (CDCl₃) 177.03, 166.65, 129.220, 132.99, 52.27,37.46.

F. Curtius Rearrangement of Methyl 2(R)-methylsuccinate: Preparation ofMethyl N-Moz-α-methyl β-alanine.

[0200]

[0201] A 5 L four necked round bottomed flask equipped with a nitrogeninlet, reflux condenser, mechanical stirrer, constant pressure additionfunnel, and thermometer adapter was charged with methyl2(R)-methylsuccinate (184.1 g, 1.26 mol), triethylamine (165.6 g, 218mL, 1.64 mol, 1.3 equivalents), and toluene (1063 mL). The solution waswarmed to 85° C. and then treated dropwise with a solution ofdiphenylphosphoryl azide (346.8 g, 1.26 mol) over a period of 1.2 h. Thesolution was maintained at that temperature for an additional 1.0 h andthen the mixture was treated with 4-methoxybenzyl alcohol (174.1 g, 1.26mol) over a 0.33 h period from the dropping funnel. The solution wasstirred at 88° C. for an additional 2.25 h and then cooled to roomtemperature. The contents of the flask were poured into a separatoryfunnel and washed with sat. aq. NaHCO₃ (2×500 mL), 0.2N HCl (2×500 mL),brine (1×500 mL), dried over anhyd. MgSO₄, filtered, and concentrated invacuo to give 302.3 g, 85% of the desired product as a slightly brownoil. 1H NMR (CDCl₃) 300 MHz 7.32(d, J=8.4 Hz, 2H), 6.91(d, J=8.4 Hz,2H), 5.2(brm, 1H), 5.05(s, 2H), 3.83(s, 3H), 3.70(s, 3H), 3.35(m, 2H),2.70(m, 2H), 1.20(d, J=7.2 Hz, 3H).

G. Hydrolysis of Methyl N-Moz-α-methyl β-alanine: Preparation ofα-methyl β-alanine Hydrochloride

[0202]

[0203] A 5 L three-necked round bottomed flask equipped with a refluxcondenser, nitrogen inlet and mechanical stirrer was charged with methylN-Moz-α-methyl β-alanine (218.6 g, 0.78 mol), glacial acetic acid (975mL) and 12N hydrochloric acid (1960 mL). The solution was then heated toreflux for 3 h. After the solution had cooled to room temperature (ca. 1h) the aqueous phase was decanted from organic residue (polymer) and theaqueous phase concentrated on a rotary evaporator. Upon addition ofacetone to the concentrated residue a slightly yellow solid formed thatwas slurried with acetone and the whit solid was isolated by filtrationon a Buchner funnel. The last traces of acetone were removed byevacuation to give 97.7 g, 90% of pure product, mp 128.5-130.5° C.[α]_(d) @ 25° C.=9.0° C. (c=2.535, Methanol). ¹H NMR (D₂O) 300 MHz3.29(dd, J=8.6, 13.0 Hz, 1H), 3.16(dd, J=5.0, 13.0m Hz, 1H), 2.94(ddq,J=7.2, 5.0, 8.6 Hz, 1H), 1.30(d, J=7.2 Hz, 3H); ¹³C NMR (D₂O) 180.84,44.56, 40.27, 17.49.

H. Preparation of N-Boc α-Methyl β-Alanine

[0204]

[0205] A solution of a-methyl b-alanine hydrochloride (97.7 g, 0.70 mol)in water (1050 mL) and dioxane (1050 mL) the pH was adjusted to 8.9 with2.9N NaOH solution. This stirring solution was then treated withdi-tert-butyl pyrocarbonate (183.3 g, 0.84 mol, 1.2 equivalents) all atonce. The pH of the solution was maintained between 8.7 and 9.0 by theperiodic addition of 2.5N NaOH solution. After 2.5 h the pH hadstabilized and the reaction was judged to be complete. The solution wasconcentrated on a rotary evaporator (the temperature was maintained at<40° C.). The excess di-tert-butyl pyrocarbonate was removed byextraction with dichloromethane and then the aqueous solution wasacidified with cold 1N HCl and immediately extracted with ethyl acetate(4×1000 mL). The combined ethyl acetate extract was washed with brine,dried over anhyd. MgSO₄, filtered and concentrated on a rotaryevaporator to give a thick oil 127.3 g, 90% crude yield that was stirredwith n-hexane whereupon crystals of pure product formed, 95.65 g, 67%,mp 76-78° C., [α]_(d) @ 25° C.=−11.8° C. (c=2.4, EtOH). A second cropwas obtained by concentration of the filtrate and dilution with hexane,15.4 g, for a combined yield of 111.05 g, 78%. ¹H NMR (acetone D₆) 300MHz 11.7 (brs, 1H), 6.05 (brs 1H), 3.35 (m, 1H), 3.22 (m, 1H), 2.50 (m,1H), 1.45(s, 9H), 1.19 (d, J=7.3 Hz, 3H); ¹³C NMR (acetone D₆) 177.01,79.28, 44.44, 40.92, 29.08, 15.50. Elemental analysis calc'd. forC₉H₁₇NO₄: C, 53.19; H, 8.42; N, 6.89. Found: C, 53.36; H, 8.46; N, 6.99.

I. Preparation of N-4-Methoxybenzyloxycarbonyl α-Methyl β-Alanine

[0206] A solution of N-4-methoxybenzyloxycarbonyl α-methyl β-alaninemethyl ester (2.81 g, 10.0 mmol) in 30 mL of 25% aqueous methanol wastreated with lithium hydroxide (1.3 equivalents) at room temperature fora period of 2 h. The solution was concentrated in vacuo and the residuetaken up in a mixture of water and ether and the phases separated andthe organic phase discarded. The aqueous phase was acidified withaqueous potassium hydrogen sulfate to pH=1.5 and then extracted threetimes with ether. The combined ethereal phase was washed with saturatedaqueous sodium chloride solution, dried over anhydrous magnesiumsulfate, filtered and concentrated in vacuo to give 2.60 g, 97% ofN-4-Methoxybenzyloxycarbonyl α-methyl β-alanine (N-Moz-AMBA) which waspurified by recrystallization from a mixture of ethyl acetate and hexaneto give 2.44 g, 91% of pure product, mp 96-97° C., MH+=268. ¹H NMR(D₆-acetone/300 MHz) 1.16 (3H, d, J=7.2 Hz), 2.70 (1H, m), 3.31 (2H, m),3.31 (3H, s), 4.99 (2H, s), 6.92 (2H, 4, J=8.7 Hz), 7.13 (2H, d, J=8.7Hz).

EXAMPLE 7

[0207] Following generally the procedure of Example 6, or utilizingprocedures known in the art, the β-amino acids set forth in Table 1 wereprepared. TABLE 1 Entry R¹ R^(1′) R^(1″) 1 —CH₃ H H 2 —CH(CH₃)₂ H H 3—C(CH₃)₃ H H 4 H H H 5 H —CH₃ H 6 H —CH₃ —CH₃ 7 H H —CO₂CH₃ 8 H H —CONH₂9 —CH₂CH₃ H H 10 —CH₂CH(CH₃)₂ H H 11 —CH₂C₆H₅ H H 12

H H 13

H H 14 —CH₂COOH H H 15 H —CH(CH₃)₂ H 16 H —CH₂CH(CH₃)₂ H 17 H

H 18 H

H 19 H

H 20 H

H 21 H —(CH₂)₃CH(C₆H₅)₂ H

EXAMPLE 8

[0208] Utilizing generally the procedure set forth in Example 6, thefollowing β-amino acid compounds were prepared.

EXAMPLE 9

[0209]N[3(s)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenylbutyl]-N-isobutylamine(370 mg. 1.0 mmole), prepared as in Example 3, is mixed with DIEA (280μL, 2.0 mmoles) and 1.0 mmole of the sulfamoyl chloride derivative ofmethyl aminoisobutyrate (2 mmol) in a 100 mL round bottomed flaskequipped with a reflux condenser, nitrogen inlet, and magnetic stir bar.The slurry is warmed to reflux and maintained at this temperature forabout 1 hour or is stirred at room temperature for about two days.

[0210] A solution of this product (1 mmole) containing 20 mL of methanoland 5 mL of acetic acid is hydrogenated over 10% palladium on carbon (80mg) for 6 h.

[0211] The free amine (0.2 mmoles) is then coupled withN-CBZ-L-asparagine (0.3 mmoles) in the presence ofN-hydroxybenzotriazole (0.3 mmoles) and EDC (0.3 mmoles) to yieldproduct.

EXAMPLE 10

[0212] Following the procedures of Examples 1-9, the compounds shown inTables 2-14 could be prepared. TABLE 2

Entry No. R R¹ R³ R¹⁶ 1 Cbz t-Butyl i-Amyl H 2 Q t-Butyl i-Amyl Methyl 3Cbz i-Butyl i-Butyl Ethyl 4 N,N-Dimethylglycine t-Butyl i-Butyliso-Propyl 5 N,N-Dimethylglycine t-Butyl i-Butyl t-Butyl 62-Quinolinylcarbonyl CH₂C(O)NH₂ i-Butyl Benzyl 7 2-QuinolinylcarbonylCH₂C(O)NH₂ i-Butyl Methyl 8 2-Quinolinylcarbonyl CH₂C(O)NH₂ i-ButylHydrogen

[0213] TABLE 3

Entry No. R R³ R¹⁶ 1 Cbz^(a) CH₃ H 2 Cbz i-Butyl CH₃ 3 Cbz i-ButylCH₂CH₃ 4 Q^(b) i-Butyl CH(CH₃)₂ 5 Cbz i-Propyl C(CH₃)₃ 6 Q i-PropylCH₂Ph 7 Cbz C₆H₅ H 8 Cbz

CH₃ 9 Cbz

C(CH₃)₃ 10 Q

H 11 Cbz

CH₂CH₃ 12 Cbz i-Butyl C(CH₃)₃ 13 Cbz i-Butyl H 14 Cbz

CH₃ 15 Cbz

CH₂CH₃ 16 Cbz

CH(CH₃)₂ 17 Cbz i-Butyl C(CH₃)₃ 18 Cbz i-Butyl CH₂Ph 19 Cbz i-amyl H 20Q -Butyl CH₃ 21 Cbz

C(CH₃)₃ 22 Cbz (CH₂)₂CH(CH₃)₂ H 23 Q i-Butyl CH₂CH₃ 24 Cbz i-amylC(CH₃)₃ 25 Q i-Butyl H 26 Cbz

CH₃ 27 Q

CH₂CH₃ 28 Cbz —(CH₂)₂CH(CH₃)₂ CH(CH₃)₂ 29 Q —(CH₂)₂CH(CH₃)₂ C(CH₃)₃ 30Cbz —CH₂C₆H₅ CH₂Ph 31 β-naphthylcarbonyl —CH₂C₆H₅ H 32 Cbz —(CH₂)₂C₆H₅CH₃ 33 Cbz —(CH₂)₂C₆H₅ C(CH₃)₃ 34 Cbz n-Butyl H 35 Cbz n-Pentyl CH₂CH₃36 Cbz n-Hexyl C(CH₃)₃ 37 Cbz

H 38 β-naphthylcarbonyl —CH₂C(CH₃)₃ CH₃ 39 β-naphthylcarbonyl—CH₂C(CH₃)₃ CH₂CH₃ 40 Cbz

CH(CH₃)₂ 41 Cbz —CH₂C₆H₅OCH₃ (para) C(CH₃)₃ 42 Cbz

CH₂Ph 43 Cbz

H 44 Cbz —(CH₂)₂C(CH₃)₃ CH₃ 45 Q —(CH₂)₂C(CH₃)₃ C(CH₃)₃ 46 Cbz —(CH₂)₄OHH 47 Q —(CH₂)₄OH CH₂CH₃ 48 Q

C(CH₃)₃ 49 Q

H 50 Cbz —CH₂CH(CH₃)₂ CH₃ 51

—CH₂CH₂CH(CH₃)₂ CH₂CH₃ 52

—CH₂CH(CH₃)₂ CH(CH₃)₂ 53

—CH₂CH(CH₃)₂ C(CH₃)₃ 54

—CH₂CH(CH₃)₂ CH₂Ph 55

—CH₂CH(CH₃)₂ H 56

—CH₂CH(CH₃)₂ CH₃ 57

—CH₂CH(CH₃)₂ C(CH₃)₃ 58

—CH₂CH(CH₃)₂ H 59

—CH₂CH(CH₃)₂ CH₂CH₃ 60

—CH₂CH(CH₃)₂ C(CH₃)₃ 61

—CH₂CH(CH₃)₂ H 62

—CH₂CH(CH₃)₂ CH₃ 63

—CH₂CH(CH₃)₂ CH₂CH₃ 64

—CH₂CH(CH₃)₂ CH(CH₃)₂ 65

—CH₂CH(CH₃)₂ C(CH₃)₃ 66

—CH₂CH(CH₃)₂ CH₂Ph 67

—CH₂CH(CH₃)₂ H 68

—CH₂CH(CH₃)₂ CH₃ 69

—CH₂CH(CH₃)₂ C(CH₃)₃ 70

—CH₂Ph H 71 Q

CH₂CH₃ 72 Q

C(CH₃)₃ 73 Q

H 74 Q

CH₃ 75 Q

H 76 Q —CH₂CH═CH₂ CH₃ 77 Q

CH₂CH₃ 78 Q

CH(CH₃)₂ 79 Q —CH₂CH₂Ph C(CH₃)₃ 80 Q —CH₂CH₂CH₂CH₂OH CH₂Ph 81 Q—CH₂CH₂N(CH₃)₂ H 82 Q

CH₃ 83 Q —CH₃ C(CH₃)₃ 84 Q —CH₂CH₂CH₂SCH₃ H 85 Q —CH₂CH₂CH₂S(O)₂CH₃CH₂CH₃ 86 Q —CH₂CH₂CH₂CH(CH₃)₂ C(CH₃)₃ 87 Q —CH₂CH₂CH(CH₃)₂ H 88 Q—CH₂CH₂CH(CH₃)₂ CH₃ 89 Q —CH₂CH₂CH₂CH(CH₃)₂ CH₂CH₃ 90 Q —CH₂CH₂CH(CH₃)₂CH(CH₃)₂ 91 Q —CH₂CH₂CH(CH₃)₂ C(CH₃)₃ 92 Q —CH₂CH₂CH(CH₃)₂ CH₂Ph 93 Q—CH₂CH₂CH(CH₃)₂ H 94 β-naphthylcarbonyl —CH₂CH₂CH(CH₃)₂ H 95β-naphthylcarbony1 —CH₂CH₂CH(CH₃)₂ CH₃ 96 Q —CH₂CH(CH₃)₂ CH₂CH₃ 97β-naphthylcarbonyl —CH₂CH₂CH(CH₃)₂ CH(CH₃)₂ 98 β-naphthylcarbonyl—CH₂CH₂CH(CH₃)₂ C(CH₃)₃ 99 β-naphthylcarbonyl —CH₂CH₂CH(CH₃)₂ CH₂Ph 100β-naphthylcarbonyl —CH₂CH₂CH(CH₃)₂ H 101 β-naphthylcarbonyl—CH₂CH₂CH(CH₃)₂ CH₃ 102 Q —CH₂CH₂CH(CH₃)₂ C(CH₃)₃ 103 β-naphthylcarbonyl—CH₂CH(CH₃)₂ H 104 Q —CH₂CH(CH₃)₂ CH₂CH₃ 105 Q —CH₂CH(CH₃)₂ C(CH₃)₃ 106Q —CH₂CH(CH₃)₂ H 107 β-naphthylcarbonyl —CH₂CH₂CH₂CH₃ CH₃ 108 Q—CH₂CH₂CH₃ CH₂CH₃ 109 Q —CH₂CH₂CH₃ CH(CH₃)₂ 110 Q —CH₂CH₂CH₃ C(CH₃)₃ 111Q —CH₂CH₂CH₃ CH₂Ph

[0214] TABLE 4

n R³ R⁸ 0 —CH₂CH(CH₃)₂ —CN 0 —CH₂CH₂CH(CH₃)₂

1 —CH₂CH₂CH(CH₃)₂

1 —CH₂CH₂CH(CH₃)₂ —C(O)N(CH₃)₂ 1 —CH₂CH₂CH(CH₃)₂ —CO₂CH₃ 2—CH₂CH₂CH(CH₃)₂

1

1

0 —CH₂CH₂CH(CH₃)₂

0

1

1 —CH₂CH(CH₃)₂ OH 1

OH 2

2

1

—SCH₃ 1

—SO₂CH₃ 1

—SO₂CH₃ 1 —CH₂CH(CH₃)₂ —CO₂CH₃ 1

—CO₂H 1

1

—SO₂Ph 1

—SO₂Ph 1 —CH₂CH₂CH(CH₃)₂

2 —CH₂CH₂CH(CH₃)₂ —N(CH₃)₂ 2 —CH₂CH₂CH(CH₃)₂

1 —CH₂CH₂CH(CH₃)₂

1 —CH₂CH₂CH(CH₃)₂

1 —CH₂CH₂CH(CH₃)₂

1 —CH₂CH₂CH(CH₃)₂

1 —CH₂CH₂CH(CH₃)₂ —N(CH₃)Ph 1 —CH₂CH₂CH(CH₃)₂

1 —CH₂CH₂CH(CH₃)₂

[0215] TABLE 5

n R³ R¹⁶ 0 isoamyl CH₂CH₃ 1 isoamyl CH₂CH₃ 2 isoamyl CH₂CH₃ 3 isoamylCH₂CH₃

[0216] TABLE 6

Entry R¹ 1 CH₂SO₂CH₃ 2 (R)-CH(OH)CH₃ 3 CH(CH₃)₂ 4 (R,S)CH₂SOCH₃ 5CH₂SO₂NH₂ 6 CH₂SCH₃ 7 CH₂CH(CH₃)₂ 8 CH₂CH₂C(O)NH₂ 9 (S)-CH(OH)CH₃ 10—CH₂C≡C—H 11 —CH₂CH═CH₂ 12 —C(CH₃)₂SCH₃ 13 —C(CH₃)₂SO₂CH₃

[0217] TABLE 7

Entry R² A 1 n-Bu Cbz -Asn 2 cyclohexylmethyl Cbz-Asn 3 n-Bu Boc 4 n-BuCbz S C₆H₅CH₂ Boc 6 P-F-C₆H₅CH₂ Cbz 7 C₆H₅CH₂ benzoyl 8 cyclohexylmethylCbz 9 n-Bu Q-Asn 10 cyclohexylmethyl Q-Asn 11 C₆H₅CH₂ Cbz-Ile 12 C₆H₅CH₂Q-Ile 13 P-F-C₆H₅CH₂ Cbz-t-BuGly 14 C₆H₅CH₂ Q-t-BuGly- 15 C₆H₅CH₂Cbz-Val 16 C₆H₅CH₂ Q-Val 17 2-naphthylmethyl Cbz-Asn 18 2-naphthylmethylQ-Asn 19 2-naphthylmethyl Cbz 20 n-Bu Cbz-Val 21 n-Bu Q-Val 22 n-BuQ-Ile 23 n-Bu Cbz-t-BuGly 24 n-Bu Q-t-BuGly 25 p-F(C₆H₄)CH₂ Q-Asn 26p-F(C₆H₄)CH₂ Cbz 27 p-F(C₅H₄)CH₂ Cbz-Asn 28 C₆H₅CH₂ Cbz-propargylglycine29 C₆H₅CH₂ Q-propargylglycine 30 C₆H₅CH₂ acetylpropargylglycine 31 n-Budimethylglycyl-t-butylglycine 32 n-Bu dimethylglycyl-isoleucine 33 n-Budimethylglycyl-valine 34 —CH₂CH₂SCH₃ dimethylglycyl-t-butylglycine 35—CH₂CH₂SCH₃ dimethylglycyl-isoleucine 36 —CH₂CH₂SCH₃dimethylglycyl-valine

[0218] TABLE 8

Entry R R¹ 1

—CH₃ 2

—CH₃ 3

—CH(CH₃)₂ 4

—CH(CH₃)₂ 5

—C(CH₃)₃ 6

—CH₃ 7

—CH₃ 8

—CH₃ 9

—CH₃ 10

—CH₃ 11

—CH₃ 12

—CH₃ 13

—CH₃ 14

—CH₃ 15

16

[0219] TABLE 9

Entry R¹ R^(1′) R^(1″) R 1 H H H

2 H H H

3 H CH₃ H

4 H CH₃ CH₃

5 H H CO₂CH₃

6 H H H

7 H H H

8 H H CONH₂ Cbz 9 H H CONH₂ 2-quinolinylcarbonyl

[0220] TABLE 10 Entry R R′ X 1 R = H R′ = H X = H 2 R = Me R′ = Me X = H3 R = H R′ = Me X = H 4 R = Me R′ = Me X = F 5 R = H R′ = Me X = F 6 R =Cbz R′ = Me X = H 7 R = H R′ = Bz X = H 8 R + R′= pyrrole X = H

[0221] TABLE 11

Entry Acyl Group (R) 1 benzyloxycarbonyl 2 tert-butoxycarbonyl 3 acetyl4 2-quinoylcarbonyl 5 phenoxyacetyl 6 benzoyl 7 methyloxaloyl 8 pivaloyl9 trifluoracetyl 10 bromoacetyl 11 hydroxyacetyl 12 morpholinylacetyl 13N,N-dimethylaminoacetyl 14 N-benzylaminoacetyl 15 N-phenylaminoacetyl 16N-benzyl-N-methylaminoacetyl 17 N-methyl-N-(2-hydroxyethyl)aminoacetyl18 N-methylcarbamoyl 19 3-methylbutyryl 20 N-isobutylcarbaxnoyl 21succinoyl (3-carboxypropionyl) 22 carbamoyl 23 N-(2-indanyl)aminoacetyl

[0222] TABLE 12

Entry R³ R¹⁶ 1 —CH₃ H 2 -i-Butyl CH₃ 3 -i-Butyl CH₂CH₃ 4 -i-PropylCH(CH₃)₂ 5 —C₆H₅ C(CH₃)₃ 6

CH₂Ph 7

H 8

CH₃ 9 -i-Butyl C(CH₃)₃ 10 -i-Butyl H 11

CH₂CH₃ 12

C(CH₃)₃ 13

H 14 n-propyl CH₃ 15 n-propyl CH₂CH₃ 16 i-Butyl CH(CH₃)₂ 17

C(CH₃)₃ 18 (CH₂)₂CH(CH₃)₂ CH₂Ph 19 i-propyl H 20 i-propyl CH₃ 21

C(CH₃)₃ 22 —(CH₂)₂CH(CH₃)₂ H 23 —CH₂C₆H₅ CH₂CH₃ 24 —(CH₂)₂C₆H₅ C(CH₃)₃25 n-Butyl H 26 n-Pentyl CH₃ 27 n-Hexyl CH₂CH₃ 28

CH(CH₃)₂ 29 —CH₂C(CH₃)₃ C(CH₃)₃ 30

CH₂Ph 31 —CH₂C₆H₅OCH₃ (para) H 32

CH₃ 33

C(CH₃)₃ 34 —(CH₂)₂C(CH₃)₃ H 35 —(CH₂)₄OH CH₂CH₃ 36

C(CH₃)₃ 37

H 38 —CH₂CH₂CH₂SCH₃ CH₃ 39 i-amyl CH₂CH₃ 40

CH(CH₃)₂ 41

CH₂C(CH₃)₃ 42 i-butyl CH₂Ph 43 —CH₂Ph —CH₂Ph 44

CH₃ 45

—CH₂Ph 46

CH₃ 47

CH₂CH₃ 48

C(CH₃)₃ 49 —CH₂CH═CH₂ H 50

CH₃ 51

CH₂CH₃ 52 —CH₂CH₂Ph CH(CH₃)₂ 53 —CH₂CH₂CH₂CH₂OH C(CH₃)₃ 54—CH₂CH₂N(CH₃)₂ CH₂Ph 55

H 56 —CH₃ CH₃ 57 —CH₂CH₂CH₂SCH₃ C(CH₃)₃ 58 —CH₂CH₂CH₂S(O)₂CH₃ H 59—CH₂CH₂CH₂CH₃ CH₂CH₃ 60 —CH₂CH₂CH₂CH₃ C(CH₃)₃ 61 —CH₂CH₂CH₂CH₃ H 62—CH₂CH₂CH₂CH₃ CH₃ 63 —CH₂CH₂CH₂CH₃ CH₂CH₃ 64 —CH₂CH₂CH₂CH₃ CH(CH₃)₂ 65—CH₂CH₂CH₂CH₃ C(CH₃)₃ 66 —CH₂CH₂CH₂CH₃ CH₂Ph 67 —CH₂CH₂CH₂CH₃ H 68—CH₂CH₂CH₂CH₃ CH₃ 69 —CH₂CH₂CH₂CH₃ C(CH₃)₃ 70 —CH₂CH₂CH₂CH₃ H 71—CH₂CH₂CH₂CH₃ CH₂CH₃ 72 —CH₂CH₂CH₂CH₃ C(CH₃)₃ 73 —CH₂CH₂CH₂CH₃

74 —CH₂CH₂CH(CH₃)₂

75 —CH₂CH(CH₃)₂

76 —CH₂CH(CH₃)₂

77 —CH₂CH(CH₃)₂

78 —CH₂CH(CH₃)₂

79 —CH₂CH₂CH₃

80 —CH₂CH₂CH₂CH₃

81 i-butyl t-butyl 82 i-amyl t-butyl 83

t-butyl 84

t-butyl

[0223] TABLE 13

Entry R¹ R¹⁶ 1 C(CH₃)₃ H 2 CH₂C≡CH CH₃ 3 C(CH₃)₂(SCH₃) CH₂CH₃ 4C(CH₃)₂(S(O)CH₃) CH(CH₃)₂ 5 C(CH₃)₂(S(O)₂CH₃) C(CH₃)₃ 6 C(CH₃)₃ CH₂Ph 7C(CH₃)₃ CH₃ 8 CH(CH₃)₂ CH₃ 9 CH(CH₂CH₃)(CH₃) C(CH₃)₃

[0224] TABLE 14

R¹ R² R³ t-Butyl Benzyl p-Fluorobenzyl i-Butyl Benzyl i-Amyl i-PropylBenzyl i-Amyl Propargyl Benzyl i-Amyl t-Butyl Benzyl i-Amyl t-ButylBenzyl Benzyl t-Butyl Benzyl n-Butyl sec-Butyl Benzyl i-AmylC(CH₃)₂(SCH₃) Benzyl i-Amyl t-Butyl p-Fluorobenzyl p-Methoxybenzyli-Butyl p-Fluorobenzyl i-Amyl i-Propyl p-Fluorobenzyl i-Amyl Propargylp-Fluorobenzyl i-Amyl t-Butyl p-Fluorobenzyl i-Amyl t-ButylP-Fluorobenzyl Benzyl t-Butyl p-Fluorobenzyl n-Butyl sec-Butylp-Fluorobenzyl i-Amyl C(CH₃)₂(SCH₃) p-Fluorobenzyl i-Amyl t-ButylCyclohexylmethyl p-Fluorobenzyl i-Butyl Cyclohexylmethyl i-Amyl i-PropylCyclohexylmethyl i-Amyl Propargyl Cyclohexylmethyl i-Amyl t-ButylCyclohexylmethyl i-Amyl t-Butyl Cyclohexylmethyl Benzyl t-ButylCyclohexylmethyl n-Butyl sec-Butyl Cyclohexylmethyl i-Amyl C(CH₃)₂(SCH₃)Cyclohexylmethyl i-Amyl t-Butyl n-Butyl Cyclohexylmethyl i-Butyl n-Butyli-Amyl i-Propyl n-Butyl i-Amyl Propargyl n-Butyl i-Amyl t-Butyl n-Butyli-Amyl t-Butyl n-Butyl Benzyl t-Butyl n-Butyl n-Butyl sec-Butyl n-Butyli-Amyl C(CH₃)₂(SCH₃) n-Butyl i-Amyl

EXAMPLE 11

[0225] The compounds of the present invention are effective HIV proteaseinhibitors. Utilizing an enzyme assay as described below, the compoundsset forth in the examples herein would be expected to inhibit the HIVenzyme. The enzyme method is described below. The substrate is2-Ile-Nle-Phe(p-NO₂)-Gln-ArgNH₂. The positive control is MVT-101(Miller, M. et al, Science, 246, 1149 (1989)] The assay conditions areas follows: Assay buffer: 20 mM sodium phosphate, pH 6.4 20% glycerol 1mM EDTA 1 mM DTT 0.1% CHAPS

[0226] The above described substrate is dissolved in DMSO, then diluted10 fold in assay buffer. Final substrate concentration in the assay is80 μM.

[0227] HIV protease is diluted in the assay buffer to a final enzymeconcentration of 12.3 nanomolar, based on a molecular weight of 10,780.

[0228] The final concentration of DMSO is 14% and the finalconcentration of glycerol is 18%. The test compound is dissolved in DMSOand diluted in DMSO to 10× the test concentration; 10 μl of the enzymepreparation is added, the materials mixed and then the mixture isincubated at ambient temperature for 15 minutes. The enzyme reaction isinitiated by the addition of 40 μl of substrate. The increase influorescence is monitored at 4 time points (0, 8, 16 and 24 minutes) atambient temperature. Each assay is carried out in duplicate wells.

EXAMPLE 12

[0229] The effectiveness of the compounds can also be determined in aCEM cell assay.

[0230] The HIV inhibition assay method of acutely infected cells is anautomated tetrazolium based colorimetric assay essentially that reportedby Pauwles et al, J. Virol. Methods, 20, 309-321 (1988). Assays can beperformed in 96-well tissue culture plates. CEM cells, a CD4+ cell line,were grown in RPMI-1640 medium (Gibco) supplemented with a 10% fetalcalf serum and were then treated with polybrene (2 μg/ml). An 80 μlvolume of medium containing 1×10⁴ cells is dispensed into each well ofthe tissue culture plate. To each well is added a 100 μl volume of testcompound dissolved in tissue culture medium (or medium without testcompound as a control) to achieve the desired final concentration andthe cells are incubated at 37° C. for 1 hour. A frozen culture of HIV-1is diluted in culture medium to a concentration of 5×10⁴ TCID₅₀ per ml(TCID₅₀ 32 the dose of virus that infects 50% of cells in tissueculture), and a 20 μL volume of the virus sample (containing 1000 TCID₅₀of virus) is added to wells containing test compound and to wellscontaining only medium (infected control cells). Several wells receiveculture medium without virus (uninfected control cells). Likewise, theintrinsic toxicity of the test compound is determined by adding mediumwithout virus to several wells containing test compound. In summary, thetissue culture plates contain the following experiments: Virus CellsDrug 1. + − − 2. + + − 3. + − + 4. + + +

[0231] In experiments 2 and 4 the final concentrations of test compoundsare 1, 10, 100 and 500 μg/ml. Either azidothymidine (AZT) ordideoxyinosine (ddI) is included as a positive drug control. Testcompounds are dissolved in DMSO and diluted into tissue culture mediumso that the final DMSO concentration does not exceed 1.5% in any case.DMSO is added to all control wells at an appropriate concentration.

[0232] Following the addition of virus, cells are incubated at 37° C. ina humidified, 5% CO₂ atmosphere for 7 days. Test compounds could beadded on days 0, 2 and 5 if desired. On day 7, post-infection, the cellsin each well are resuspended and a 100 μl sample of each cell suspensionis removed for assay. A 20 μL volume of a 5 mg/ml solution of3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) isadded to each 100 μL cell suspension, and the cells are incubated for 4hours at 27° C. in a 5% CO₂ environment. During this incubation, MTT ismetabolically reduced by living cells resulting in the production in thecell of a colored formazan product. To each sample is added 100 μl of10% sodium dodecylsulfate in 0.01 N HCl to lyse the cells, and samplesare incubated overnight. The absorbance at 590 nm is determined for eachsample using a Molecular Devices microplate reader. Absorbance valuesfor each set of wells is compared to assess viral control infection,uninfected control cell response as well as test compound bycytotoxicity and antiviral efficacy.

[0233] The compounds of the present invention are effective antiviralcompounds and, in particular, are effective retroviral inhibitors asshown above. Thus, the subject compounds are effective HIV proteaseinhibitors. It is contemplated that the subject compounds will alsoinhibit other retroviruses such as other lentiviruses in particularother strains of HIV, e.g. HIV-2, human T-cell leukemia virus,respiratory syncitial virus, simia immunodeficiency virus, felineleukemia virus, feline immuno-deficiency virus, hepadnavirus,cytomegalovirus and picornavirus. Thus, the subject compounds areeffective in the treatment and/or proplylaxis of retroviral infections.

[0234] Compounds of the present invention can possess one or moreasymmetric carbon atoms and are thus capable of existing in the form ofoptical isomers as well as in the form of racemic or nonracemic mixturesthereof. The optical isomers can be obtained by resolution of theracemic mixtures according to conventional processes, for example byformation of diastereoisomeric salts by treatment with an opticallyactive acid or base. Examples of appropriate acids are tartaric,diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric andcamphorsulfonic acid and then separation of the mixture ofdiastereoisomers by crystallization followed by liberation of theoptically active bases from these salts. A different process forseparation of optical isomers involves the use of a chiralchromatography column optimally chosen to maximize the separation of theenantiomers. Still another available method involves synthesis ofcovalent diastereoisomeric molecules by reacting compounds of Formula Iwith an optically pure acid in an activated form or an optically pureisocyanate. The synthesized diastereoisomers can be separated byconventional means such as chromatography, distillation, crystallizationor sublimation, and then hydrolyzed to deliver the enantiomerically purecompound. The optically active compounds of Formula I can likewise beobtained by utilizing optically active starting materials. These isomersmay be in the form of a free acid, a free base, an ester or a salt.

[0235] The compounds of the present invention can be used in the form ofsalts derived from inorganic or organic acids. These salts include butare not limited to the following: acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate,ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, mesylate andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as lower alkyl halides, such as methyl,ethyl, propyl, and butyl chloride, bromides, and iodides; dialkylsulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides, aralkyl halides like benzyl and phenethylbromides, and others. Water or oil-soluble or dispersible products arethereby obtained.

[0236] Examples of acids which may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulphuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, succinic acid and citric acid. Otherexamples include salts with alkali metals or alkaline earth metals, suchas sodium, potassium, calcium or magnesium or with organic bases.

[0237] Total daily dose administered to a host in single or divideddoses may be in amounts, for example, from 0.001 to 10 mg/kg body weightdaily and more usually 0.01 to 1 mg. Dosage unit compositions maycontain such amounts of submultiples thereof to make up the daily dose.

[0238] The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration.

[0239] The dosage regimen for treating a disease condition with thecompounds and/or compositions of this invention is selected inaccordance with a variety of factors, including the type, age, weight,sex, diet and medical condition of the patient, the severity of thedisease, the route of administration, pharmacological considerationssuch as the activity, efficacy, pharmacokinetic and toxicology profilesof the particular compound employed, whether a drug delivery system isutilized and whether the compound is administered as part of a drugcombination. Thus, the dosage regimen actually employed may vary widelyand therefore may deviate from the preferred dosage regimen set forthabove.

[0240] The compounds of the present invention may be administeredorally, parenterally, by inhalation spray, rectally, or topically indosage unit formulations containing conventional nontoxicpharmaceutically acceptable carriers, adjuvants, and vehicles asdesired. Topical administration may also involve the use of transdermaladministration such as transdermal patches or iontophoresis devices. Theterm parenteral as used herein includes subcutaneous injections,intravenous, intramuscular, intrasternal injection, or infusiontechniques.

[0241] Injectable preparations, for example, sterile injectable aqueousor oleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

[0242] Suppositories for rectal administration of the drug can beprepared by mixing the drug with a suitable nonirritating excipient suchas cocoa butter and polyethylene glycols which are solid at ordinarytemperatures but liquid at the rectal temperature and will thereforemelt in the rectum and release the drug.

[0243] Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose lactose or starch. Such dosage forms may also comprise, as innormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

[0244] Liquid dosage forms for oral administration may includepharmaceutically acceptable emulsions, solutions, suspensions, syrups,and elixirs containing inert diluents commonly used in the art, such aswater. Such compositions may also comprise adjuvants, such as wettingagents, emulsifying and suspending agents, and sweetening, flavoring,and perfuming agents.

[0245] While the compounds of the invention can be administered as thesole active pharmaceutical agent, they can also be used in combinationwith one or more immunomodulators, antiviral agents or otherantiinfective agents. For example, the compounds of the invention can beadministered in combination with AZT, DDI, DDC or with glucosidaseinhibitors, such as N-butyl-1-deoxynojirimycin or prodrugs thereof, forthe prophylaxis and/or treatment of AIDS. When administered as acombination, the therapeutic agents can be formulated as separatecompositions which are given at the same time or different times, or thetherapeutic agents can be given as a single composition.

[0246] The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims.

[0247] From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:
 1. A compound represented by the formula:

or a pharmaceutically acceptable salt, prodrug or ester thereof wherein:R represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,aralkyl, alkoxycarbonyl, alkoxycarbonyl, aryloxyalkyl,heteroaryloxyalkyl, aralkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl,cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl, aralkanoyl,aroyl, aryloxycarbonyl, aryloxycarbonylalkyl, aryloxyalkanoyl,heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylalkanoyl,heterocyclylalkoxycarbonyl, heteroaralkanoyl, heteroaralkoxycarbonyl,heteroaryloxycarbonyl, heteroaroyl, hydroxyalkyl, aminocarbonyl,aminoalkanoyl, and mono- and disubstituted aminocarbonyl and mono- anddisubstituted aminoalkanoyl radicals wherein the substituents areselected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkyalkylradicals, or wherein said aminocarbonyl and aminoalkanoyl radicals aredisubstituted, said substituents along with the nitrogen atom to whichthey are attached form a heterocycloalkyl or heteroaryl radical; R′represents hydrogen, radicals as defined for R³ or R″SO₂— wherein R″represents radicals as defined for R³; or R and R′ together with thenitrogen to which they are attached represent heterocycloalkyl andheteroaryl radicals; R¹ represents hydrogen, —CH₂SO₂NH₂, —CH₂CO₂CH₃,—CO₂CH₃, —CONH₂, —CH₂C(O)NHCH₃, —C(CH₃)₂(SH), —C(CH₃)₂(SCH₃),—C(CH₃)₂(S[O]CH₃), —C(CH₃)₂(S[O]₂CH₃), alkyl, haloalkyl, alkenyl,alkynyl and cycloalkyl radicals, and amino acid side chains selectedfrom asparagine, S-methyl cysteine and methionine and the sulfoxide (SO)and sulfone (SO₂) derivatives thereof, isoleucine, allo-isoleucine,alanine, leucine, tert-leucine, phenylalanine, ornithine, histidine,norleucine, glutamine, threonine, glycine, allo-threonine, serine,O-alkyl serine, aspartic acid, beta-cyanoalanine and valine side chains;R¹′ and R¹″ independently represent hydrogen and radicals as defined forR¹, or one of R¹′ and R¹″, together with R¹ and the carbon atoms towhich R¹, R¹′ and R¹″ are attached, represent a cycloalkyl radical; R²represents alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkylradicals, which radicals are optionally substituted with a groupselected from alkyl and halogen radials, —NO₂, —CN, —CF₃, —OR⁹ and —SR⁹,wherein R⁹ represents hydrogen and alkyl radicals, and halogen radicals;R³ represents alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl,heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl andmono- and disubstituted aminoalkyl radicals, wherein said substituentsare selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroaralkyl, heterocycloalkyl, and heterocycloalkylalkylradicals, or in the case of a disubstituted aminoalkyl radical, saidsubstituents along with the nitrogen atom to which they are attached,form a heterocycloalkyl or a heteroaryl radical, and thioalkyl,alkylthioalkyl and arylthioalkyl radicals and the sulfone and sulfoxidederivatives thereof; R⁴ represents hydrogen and radicals as defined byR³; R⁶ represents hydrogen and alkyl radicals; R⁷ and R⁷′ independentlyrepresent hydrogen and radicals as defined for R³; amino acid sidechains selected from the group consisting of valine, isoleucine,glycine, alanine, allo-isoleucine, asparagine, leucine, glutamine, andt-butylglycine; radicals represented by the formulas —C(O)R¹⁶, —CO₂R¹⁶,—SO₂R¹⁶, —SR¹⁶, —CONR¹⁶R¹⁷, —CF₃ and —NR¹⁶R¹⁷; or R⁷ and R⁷′ togetherwith the carbon atom to which they are attached form a cycloalkylradical; R⁸ represents cyano, hydroxyl, alkyl, alkoxy, cycloalkyl, aryl,aralkyl, heterocycloalkyl and heteroaryl radicals and radicalsrepresented by the formulas C(O)R¹⁶, CO₂R¹⁶, SO₂R¹⁶, SR¹⁶, CONR¹⁶R¹⁷,CF₃ and NR¹⁶R¹⁷; wherein R¹⁶ and R¹⁷ independently represent hydrogenand radicals as defined for R³, or R¹⁶ and R¹⁷ together with a nitrogento which they are attached in the formula NR¹⁶R¹⁷ representheterocycloalkyl and heteroaryl radicals; x represents 1 or 2; nrepresents an integer of from 0 to 6; t represents either 0, 1 or 2; andY represents O, S and NR¹⁵ wherein R¹⁵ represents hydrogen and radicalsas defined for R³;
 2. Compound represented by the formula:

wherein: R represents hydrogen, alkyl, alkenyl, cycloalkyl,hydroxyalkyl, aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl,alkoxycarbonyl, alkoxyalkyl, aralkoxycarbonyl, alkylcarbonyl,cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl,alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl,aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl,heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroaralkanoyl,heteroaralkoxycarbonyl, heteroaryloxy-carbonyl, heteroaroyl,aminocarbonyl, aminoalkanoyl, and mono- and disubstituted aminocarbonyland mono- and disubstituted aminoalkanoyl radicals wherein thesubstituents are selected from alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl,heterocycloalkyalkyl radicals, or where said aminoalkanoyl radical isdisubstituted, said substituents along with the nitrogen atom to whichthey are attached form a heterocycloalkyl or heteroaryl radical; R′represents hydrogen and radicals as defined for R³ or R and R′ togetherwith the nitrogen to which they are attached represent heterocycloalkyland heteroaryl radical; R¹ represents hydrogen, —CH₂SO₂NH₂, —CH₂CO₂CH₃,—CO₂CH₃, —CONH₂, —CH₂C(O)NHCH₃, —C(CH₃)₂(SH), —C(CH₃)₂(SCH₃),—C(CH₃)₂(S[O]CH₃), —C(CH₃)₂(S[O]₂CH₃), alkyl, haloalkyl, alkenyl,alkynyl and cycloalkyl radicals, and amino acid side chains selectedfrom asparagine, S-methyl cysteine and methionine and the sulfoxide (SO)and sulfone (SO₂) derivatives thereof, isoleucine, allo-isoleucine,alanine, leucine, tert-leucine, phenylalanine, ornithine, histidine,norleucine, glutamine, threonine, glycine, allo-threonine, serine,O-methyl serine, aspartic acid, beta-cyanoalanine and valine sidechains; R² represents alkyl, aryl, cycloalkyl, cycloalkylalkyl andaralkyl radicals, which radicals are optionally substituted with a groupselected from alkyl and halogen radials, —NO₂, —C≡N, CF₃, —OR⁹, —SR⁹,wherein R⁹ represents hydrogen and alkyl radicals; R³ represents alkyl,haloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl,aryl, aralkyl, heteroaralkyl, aminoalkyl and mono- and disubstitutedaminoalkyl radicals, wherein said substituents are selected from alkyl,aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl,heterocycloalkyl, and heterocycloalkylalkyl radicals, or in the case ofa disubstituted aminoalkyl radical, said substituents along with thenitrogen atom to which they are attached, form a heterocycloalkyl or aheteroaryl radical, and thioalkyl, alkylthioalkyl and arylthioalkyl andthe sulfone and sulfoxide derivatives thereof; R⁴ represents hydrogenand radicals as defined by R³; R⁷ and R⁷′ independently representradicals as defined for R³ and amino acid side chains selected from thegroup consisting of valine, isoleucine, glycine, alanine,allo-isoleucine, asparagine, leucine, glutamine, and t-butylglycine orR⁷ and R⁷′ together with the carbon atom to which they are attached forma cycloalkyl radical; R⁸ represents cyano, hydroxyl, alkyl, alkoxy,cycloalkyl, aryl, aralkyl, heterocycloalkyl and heteroaryl radicals andradicals represented by the formulas C(O)R¹⁶, CO₂R¹⁶, SO₂R¹⁶, SR¹⁶,CONR¹⁶R¹⁷, CF₃ and NR¹⁶R¹⁷; wherein R¹⁶ and R¹⁷ independently representhydrogen and radicals as defined for R³, or R¹⁶ and R¹⁷ together with anitrogen to which they are attached in the formula NR¹⁶R¹⁷ representheterocycloalkyl and heteroaryl radicals; n represents an integer offrom 0 to
 6. 3. Compound of claim 2 wherein R represents hydrogen,alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxycarbonyl,aralkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl,cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl, aralkanoyl,aroyl, aryloxycarbonyl, aryloxycarbonylalkyl, aryloxyalkanoyl,heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylalkanoyl,heterocyclylalkoxycarbonyl, heteroaralkanoyl, heteroaralkoxycarbonyl,heteroaryloxy-carbonyl, heteroaroyl, aryloxyalkyl, heteroaryloxyalkyl,hydroxyalkyl, aminocarbonyl, aminoalkanoyl, and mono- and disubstitutedaminocarbonyl and mono- and disubstituted aminoalkanoyl radicals whereinthe substituents are selected from alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl,heterocycloalkyalkyl radicals, or where said aminoalkanoyl radical isdisubstituted, said substituents along with the nitrogen atom to whichthey are attached form a heterocycloalkyl or heteroaryl radical; R′represents hydrogen and radicals as defined for R³ or R and R′ togetherwith the nitrogen to which they are attached represent heterocycloalkyland heteroaryl radical; R¹ represents CH₂C(O)NHCH₃, C(CH₃)₂(SCH₃),C(CH₃)₂(S[O]CH₃), C(CH₃)₂(S[O]₂CH₃), alkyl, alkenyl and alkynylradicals, and amino acid side chains selected from the group consistingof asparagine, valine, threonine, allo-threonine, isoleucine,tert-leucine, S-methyl cysteine and the sulfone and sulfoxidederivatives thereof, alanine, and allo-isoleucine; R² represents alkyl,cycloalkylalkyl and aralkyl radicals, which radicals are optionallysubstituted with halogen radicals and radicals represented by theformula —OR⁹ and —SR⁹ wherein R⁹ represents alkyl radicals; and R³represents alkyl, haloalkyl, alkenyl, alkoxyalkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyland heteroaralkyl radicals; R⁴ represents hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl,heterocycloalkyl and heterocycloalkylalkyl radicals; R⁷ and R⁷′independently represent alkyl and aralkyl radicals or together with thecarbon atom to which they are attached form a cycloalkyl radical havingfrom 3 to 8 carbon atoms; R⁸ represents alkylcarbonyl, aryl, aroyl,aryloxy, aralkanoyl, cyano, hydroxycarbonyl, arylsulfonyl,alkylsulfonyl, alkylthio, hydroxyl, alkoxy, heteroaryl,dialkylaminocarbonyl, dialkylamino, cycloalkylamino, heterocyclylaminoand alkoxycarbonyl radicals; and n is an integer of from 0 to
 6. 4.Compound of claim 2 wherein R represents alkoxycarbonyl,aralkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl,cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl, aralkanoyl,aroyl, aryloxycarbonyl, aryloxycarbonylalkyl, aryloxyalkanoyl,heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylalkanoyl,heterocyclylalkoxycarbonyl, heteroaralkanoyl, heteroaralkoxycarbonyl,heteroaryloxy-carbonyl, heteroaroyl, aminocarbonyl, aminoalkanoyl, andmono- and disubstituted aminocarbonyl and mono- and disubstitutedaminoalkanoyl radicals wherein the substituents are selected from alkyl,aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl,heterocycloalkyl, heterocycloalkyalkyl radicals, or where saidaminoalkanoyl radical is disubstituted, said substituents along with thenitrogen atom to which they are attached form a heterocycloalkyl orheteroaryl radical; R′ represents hydrogen and radicals as defined forR³ or R and R′ together with the nitrogen to which they are attachedrepresent heterocycloalkyl and heteroaryl radical; R¹ representsCH₂C(O)NHCH₃, C(CH₃)₂(SCH₃), C(CH₃)₂(S[O]CH₃), C(CH₃)₂(S[O]₂CH₃),methyl, propargyl, t-butyl, isopropyl and sec-butyl radicals, and aminoacid side chains selected from the group consisting of asparagine,valine, S-methyl cysteine, allo-iso-leucine, iso-leucine, and beta-cyanoalanine side chains; R² represents CH₃SCH₂CH₂—, iso-butyl, n-butyl,benzyl, 4-fluorobenzyl, 2-naphthylmethyl and cyclohexylmethyl radicals;R³ represents propyl, isoamyl, n-butyl, isobutyl, cyclohexyl,cyclohexylmethyl, benzyl and pyridylmethyl radicals; R⁴ representshydrogen and methyl, ethyl, i-propyl, propyl, n-butyl, t-butyl,1,1-dimethylpropyl, cyclohexyl and phenyl radicals; R⁷ and R⁷′independently represent methyl, ethyl, propyl and butyl radicals, ortogether with the carbon atom to which they are attached form acyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radical; R⁸represents methylcarbonyl, phenyl, hydroxy, methoxy, cyano,methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, t-butoxycarbonyl,benzyloxycarbonyl, carboxyl, methoxycarbonyl, methylsulfonyl,methylthio, phenylsulfonyl, phenyl, 2-, 3- or 4-pyridyl, 2-, 3- or4-pyridyl N-oxide, N,N-dimethylamino, 1-piperidinyl, 4-morpholinyl,4-(N-methyl)piperazinyl and 1-pyrrolidinyl; and n represents an integerof from 0 to
 6. 5. A pharmaceutical composition comprising a compound ofclaim 1 and a pharmaceutically acceptable carrier.
 6. A pharmaceuticalcomposition comprising a compound of claim 2 and a pharmaceuticallyacceptable carrier.
 7. Method of inhibiting a retroviral proteasecomprising administering a protease inhibiting amount of a compositionof claim
 5. 8. Method of claim 7 wherein the retroviral protease is HIVprotease.
 9. Method of treating a retroviral infection comprisingadministering an effective amount of a composition of claim
 5. 10.Method of claim 9 wherein the retroviral infection is an HIV infection.11. Method for treating AIDS comprising administering an effectiveamount of a composition of claim
 5. 12. Method of inhibiting aretroviral protease comprising administering a protease inhibitingamount of a composition of claim
 6. 13. Method of claim 12 wherein theretroviral protease is HIV protease.
 14. Method of treating a retroviralinfection comprising administering an effective amount of a compositionof claim
 6. 15. Method of claim 12 wherein the retroviral infection isan HIV infection.
 16. method for treating AIDS comprising administeringan effective amount of a composition of claim
 6. 17. Compoundrepresented by the formula:

wherein: R represents hydrogen, alkyl, alkenyl, cycloalkyl, aryl,aralkyl, arylpxyalkyl, heteroaryloxyalkyl, hydroxyalkyl, alkoxycarbonyl,aralkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl,cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl, aralkanoyl,aroyl, aryloxycarbonyl, aryloxycarbonylalkyl, alkoxyalkyl,aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl,heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroaralkanoyl,heteroaralkoxycarbonyl, heteroaryloxy-carbonyl, heteroaroyl,aminocarbonyl, aminoalkanoyl, and mono- and disubstituted aminocarbonyland mono- and disubstituted aminoalkanoyl radicals wherein thesubstituents are selected from alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl,heterocycloalkyalkyl radicals, or where said aminoalkanoyl radical isdisubstituted, said substituents along with the nitrogen atom to whichthey are attached form a heterocycloalkyl or heteroaryl radical; R′represents hydrogen and radicals as defined for R³ or R and R′ togetherwith the nitrogen to which they are attached represent heterocycloalkyland heteroaryl radical; R¹ represents hydrogen, —CH₂SO₂NH₂, —CH₂CO₂CH₃,—CO₂CH₃, —CONH₂, —CH₂C(O)NHCH₃, —C(CH₃)₂(SH), —C(CH₃)₂(SCH₃),—C(CH₃)₂(S[O]CH₃), —C(CH₃)₂(S[O]₂CH₃), alkyl, haloalkyl, alkenyl,alkynyl and cycloalkyl radicals, and amino acid side chains selectedfrom asparagine, S-methyl cysteine and methionine and the sulfoxide (SO)and sulfone (SO₂) derivatives thereof, isoleucine, allo-isoleucine,alanine, leucine, tert-leucine, phenylalanine, ornithine, histidine,norleucine, glutamine, threonine, glycine, allo-threonine, serine,aspartic acid, beta-cyano alanine and valine side chains; R² representsalkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkyl radicals, whichradicals are optionally substituted with a group selected from alkyl andhalogen radicals, —NO₂, —C≡N, CF₃, —OR⁹, —SR⁹, wherein R⁹ representshydrogen and alkyl radicals; R³ represents alkyl, haloalkyl, alkenyl,alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl,heteroaralkyl, aminoalkyl and mono- and disubstituted aminoalkylradicals, wherein said substituents are selected from alkyl, aryl,aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl,heterocycloalkyl, and heterocycloalkylalkyl radicals, or in the case ofa disubstituted aminoalkyl radical, said substituents along with thenitrogen atom to which they are attached, form a heterocycloalkyl or aheteroaryl radical, and thioalkyl, alkylthioalkyl and arylthioalkylradicals and the sulfone and sulfoxide derivatives thereof; R⁴represents hydrogen and radicals as defined for R³; R⁷ and R⁷′independently represent radicals as defined for R³ and amino acid sidechains selected from the group consisting of valine, isoleucine,glycine, alanine, allo-isoleucine, asparagine, leucine, glutamine, andt-butylglycine or R⁷ and R⁷′ together with the carbon atom to which theyare attached form a cycloalkyl radical; R⁸ represents cyano, hydroxyl,alkyl, alkoxy, cycloalkyl, aryl, aralkyl, heterocycloalkyl andheterbaryl radicals and radicals represented by the formulas C(O)R¹⁶,CO₂R¹⁶, SO₂R¹⁶, SR¹⁶, CONR¹⁶R¹⁷, CF₃ and NR¹⁶R¹⁷; wherein R¹⁶ and R¹⁷independently represent hydrogen and radicals as defined for R³, or R¹⁶and R¹⁷ together with a nitrogen to which they are attached in theformula NR¹⁶R¹⁷ represent heterocycloalkyl and heteroaryl radicals; nrepresents an integer of from 0 to
 6. 18. Compound of claim 17 wherein Rrepresents hydrogen, alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl,cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl,alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl,aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl,heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroaralkanoyl,heteroaralkoxycarbonyl, heteroaryloxy-carbonyl, heteroaroyl, alkyl,alkenyl, cycloalkyl, aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl,hydroxyalkyl, aminocarbonyl, aminoalkanoyl, and mono- and disubstitutedaminocarbonyl and mono- and disubstituted aminoalkanoyl radicals whereinthe substituents are selected from alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl,heterocycloalkyalkyl radicals, or where said aminoalkanoyl radical isdisubstituted, said substituents along with the nitrogen atom to whichthey are attached form a heterocycloalkyl or heteroaryl radical; R′represents hydrogen and radicals as defined for R³ or R and R′ togetherwith the nitrogen to which they are attached represent heterocycloalkyland heteroaryl radical; R¹ represents hydrogen, alkyl, alkenyl andalkynyl radicals, and amino acid side chains selected from the groupconsisting of asparagine, valine, threonine, allo-threonine, isoleucine,tert-leucine, S-methyl cysteine and the sulfone and sulfoxidederivatives thereof, alanine, and allo-isoleucine; R² represents alkyl,cycloalkylalkyl and aralkyl radicals, which radicals are optionallysubstituted with halogen radicals and radicals represented by theformula —OR⁹ and —SR⁹ wherein R⁹ represents hydrogen and alkyl andhalogen radicals; R³ represents alkyl, halalkyl, alkenyl, alkoxyalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,aryl, aralkyl, heteroaryl and heteroaralkyl radicals; R⁴ representshydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, aralkyl,heteroaralkyl, heterocycloalkyl and heterocycloalkylalkyl radicals; R⁷and R⁷′ independently represent alkyl and aralkyl radicals or togetherwith the carbon atom to which they are attached form a cycloalkylradical having from 3 to 8 carbon atoms; R⁸ represents alkylcarbonyl,aryl, aroyl, aryloxy, aralkanoyl, cyano, hydroxycarbonyl, arylsulfonyl,alkylsulfonyl, alkylthio, hydroxyl, alkoxy, heteroaryl,dialkylaminocarbonyl, dialkylamino, cycloalkylamino, heterocyclylaminoand alkoxycarbonyl radicals; and n represents an integer of from 0 to 6.19. Compound of claim 17 wherein R represents hydrogen, alkoxycarbonyl,aralkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl,cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl, aralkanoyl,aroyl, aryloxycarbonyl, aryloxycarbonylalkyl, aryloxyalkanoyl,heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylalkanoyl,heterocyclylalkoxycarbonyl, heteroaralkanoyl, heteroaralkoxycarbonyl,heteroaryloxy-carbonyl, heteroaroyl, aminocarbonyl, aminoalkanoyl, andmono- and disubstituted aminocarbonyl and mono- and disubstitutedaminoalkanoyl radicals wherein the substituents are selected from alkyl,aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl,heterocycloalkyl, heterocycloalkyalkyl radicals, or where saidaminoalkanoyl radical is disubstituted, said substituents along with thenitrogen atom to which they are attached form a heterocycloalkyl orheteroaryl radical; R′ represents hydrogen and radicals as defined forR³ or R and R′ together with the nitrogen to which they are attachedrepresent heterocycloalkyl and heteroaryl radical; R¹ representshydrogen, methyl, propargyl, t-butyl, isopropyl and sec-butyl radicals,and amino acid side chains selected from the group consisting ofasparagine, valine, S-methyl cysteine, allo-iso-leucine, iso-leucine,threonine, serine, aspartic acid, beta-cyano alanine, and allo-threonineside chains; R² represents CH₃SCH₂CH₂—, iso-butyl, n-butyl, benzyl,4-fluorobenzyl, 2-naphthylmethyl and cyclohexylmethyl radicals; R³represents propyl, isobutyl, isoamyl, n-butyl, n-propyl, cyclohexyl,cyclohexylmethyl, benzyl and pyridylmethyl radicals; R⁴ representshydrogen and methyl, ethyl, i-propyl, n-butyl, t-butyl,1,1-dimethylpropyl, cyclohexyl and phenyl radicals; R⁷ and R⁷′independently represent methyl, ethyl, propyl and butyl radicals, ortogether with the carbon atom to which they are attached form acyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radical; R⁸represents methylcarbonyl, phenyl, hydroxy, methoxy, cyano,methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, t-butoxycarbonyl,benzyloxycarbonyl, carboxyl, methoxycarbonyl, methylsulfonyl,methylthio, phenylsulfonyl, phenyl, 2-, 3- or 4-pyridyl, 2-, 3- or4-pyridyl N-oxide, N,N-dimethylamino, 1-piperidinyl, 4-morpholinyl,4-(N-methyl)piperazinyl and 1-pyrrolidinyl; and n represents an integerof from 0 to
 6. 20. A pharmaceutical composition comprising a compoundof claim 17 and a pharmaceutically acceptable carrier.
 21. Method ofinhibiting a retroviral protease comprising administering a proteaseinhibiting amount of a composition of claim
 20. 22. Method of claim 21wherein the retroviral protease is HIV protease.
 23. Method of treatinga retroviral infection comprising administering an effective amount of acomposition of claim
 20. 24. Method of claim 23 wherein the retroviralinfection is an HIV infection.
 25. Method for treating AIDS comprisingadministering an effective amount of a composition of claim
 20. 26.Compound represented by the formula:

wherein: R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl,alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl,cycloalkylalkanoyl, alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl,aryloxycarbonylalkyl, alkoxyalkyl, aryloxyalkanoyl,heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylalkanoyl,heterocyclylalkoxycarbonyl, heteroaralkanoyl, heteroaralkoxycarbonyl,heteroaryloxy-carbonyl, heteroaroyl, alkyl, alkenyl, cycloalkyl, aryl,aralkyl, aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl, aminocarbonyl,aminoalkanoyl, and mono- and disubstituted aminocarbonyl and mono- anddisubstituted aminoalkanoyl radicals wherein the substituents areselected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkyalkylradicals, or where said aminoalkanoyl radical is disubstituted, saidsubstituents along with the nitrogen atom to which they are attachedform a heterocycloalkyl or heteroaryl radical; R′ represents hydrogenand radicals as defined for R³ or R and R′ together with the nitrogen towhich they are attached represent heterocycloalkyl and heteroarylradical; R¹ represents hydrogen, —CH₂SO₂NH₂, —CH₂CO₂CH₃, —CO₂CH₃,—CONH₂, —CH₂C(O)NHCH₃, —C(CH₃)₂(SH), —C(CH₃)₂(SCH₃), —C(CH₃)₂(S[O]CH₃),—C(CH₃)₂(S[O]₂CH₃), alkyl, haloalkyl, alkenyl, alkynyl and cycloalkylradicals, and amino acid side chains selected from asparagine, S-methylcysteine and methionine and the sulfoxide (SO) and sulfone (SO₂)derivatives thereof, isoleucine, allo-isoleucine, alanine, leucine,tert-leucine, phenylalanine, ornithine, histidine, norleucine,glutamine, threonine, glycine, allo-threonine, serine, aspartic acid,beta-cyano alanine and valine side chains; R¹′ and R¹″ independentlyrepresent hydrogen and radicals as defined for R¹, or one of R¹′ andR¹″, together with R¹ and the carbon atoms to which R¹, R¹′ and R¹″ areattached, represent a cycloalkyl radical; R² represents alkyl, aryl,cycloalkyl, cycloalkylalkyl and aralkyl radicals, which radicals areoptionally substituted with a group selected from alkyl and halogenradials; —NO₂, —C≡N, CF₃, —OR⁹ and —SR⁹, wherein R⁹ represents hydrogenand alkyl radicals; R³ represents alkyl, haloalkyl, alkenyl, alkynyl,hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl,heteroaralkyl, aminoalkyl and mono- and disubstituted aminoalkylradicals, wherein said substituents are selected from alkyl, aryl,aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl,heterocycloalkyl, and heterocycloalkylalkyl radicals, or in the case ofa disubstituted aminoalkyl radical, said substituents along with thenitrogen atom to which they are attached, form a heterocycloalkyl or aheteroaryl radical, and thioalkyl, alkylthioalkyl and arylthioalkylradicals and the sulfone and sulfoxide derivatives thereof; R⁴represents hydrogen and radicals as defined by R³; R⁷ and R⁷′independently represent radicals as defined for R³ and amino acid sidechains selected from the group consisting of valine, isoleucine,glycine, alanine, allo-isoleucine, asparagine, leucine, glutamine, andt-butylglycine or R⁷ and R⁷′ together with the carbon atom to which theyare attached form a cycloalkyl radical; R⁸ represents cyano, hydroxyl,alkyl, alkoxy, cycloalkyl, aryl, aralkyl, heterocycloalkyl andheteroaryl radicals and radicals represented by the formulas C(O)R¹⁶,CO₂R¹⁶, SO₂R¹⁶, SR¹⁶, CONR¹⁶R¹⁷, CF₃ and NR¹⁶R¹⁷; wherein R¹⁶ and R¹⁷independently represent hydrogen and radicals as defined for R³, or R¹⁶and R¹⁷ together with a nitrogen to which they are attached in theformula NR¹⁶R¹⁷ represent heterocycloalkyl and heteroaryl radicals; nrepresents an integer of from 0 to
 6. 27. Compound of claim 26 wherein Rrepresents an arylalkanoyl, heteroaroyl, aryloxyalkanoyl,aryloxycarboryl, alkanoyl, aminocarbonyl, mono-substitutedaminoalkanoyl, or disubstituted aminoalkanoyl, or mono- ordialkylaminocarbonyl radical; R′ represents hydrogen and radicals asdefined for R³ or R and R′ together with the nitrogen to which they areattached represent a heterocycloalkyl or heteroaryl radical; R¹, R¹′ andR¹″ independently represent hydrogen and alkyl radicals having from 1 toabout 4 carbon atoms, alkenyl, alkynyl, aralkyl radicals, and radicalsrepresented by the formula —CH₂C(O)R″ or —C(O)R″ wherein R″ representsR³⁸, —NR³⁸R³⁹ and OR³⁸ wherein R³⁸ and R³⁹ independently representhydrogen and alkyl radicals having from 1 to about 4 carbon atoms; R²represents alkyl, cycloalkylalkyl and aralkyl radicals, which radicalsare optionally substituted with halogen radicals and radicalsrepresented by the formula —OR⁹ and —SR⁹ wherein R⁹ represents hydrogenand alkyl radicals; and R³ represents alkyl, haloalkyl, alkenyl,alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl andheteroaralkyl radicals; R⁴ represents hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl,heterocycloalkyl and heterocycloalkylalkyl radicals; R⁷ and R⁷′independently represent alkyl and aralkyl radicals or together with thecarbon atom to which they are attached form a cycloalkyl radical havingfrom 3 to 8 carbon atoms; R⁸ represents alkylcarbonyl, aryl, aroyl,aryloxy, aralkanoyl, cyano, hydroxycarbonyl, arylsulfonyl,alkylsulfonyl, alkylthio, hydroxyl, alkoxy, heteroaryl,dialkylaminocarbonyl, dialkylamino, cycloalkylamino, heterocyclylaminoand alkoxycarbonyl radicals.
 28. Compound of claim 26 wherein Rrepresents an arylalkanoyl, aryloxycarbonyl, aryloxyalkanoyl,heteroaroyl, alkanoyl, aminocarbonyl, mono-substituted aminoalkanoyl, ordisubstituted aminoalkanoyl, or mono- or dialkylaminocarbonyl radical;R′ represents hydrogen and radicals as defined for R³ or R and R′together with the nitrogen to which they are attached represent aheterocycloalkyl or heteroaryl radical; R¹, R¹′ and R¹″ independentlyrepresent hydrogen, methyl, ethyl, benzyl, phenylpropyl, —C(O)NH₂ andpropargyl radicals; R² represents CH₃SCH₂CH₂—, iso-butyl, n-butyl,benzyl, 4-fluorobenzyl, 2-naphthylmethyl and cyclohexylmethyl radicals;R³ represents propyl, isobutyl, isoamyl, n-butyl, n-propyl, cyclohexyl,cyclohexylmethyl, benzyl and pyridylmethyl radicals; R⁴ representshydrogen and methyl, ethyl, i-propyl, n-propyl, n-butyl, t-butyl,1,1-dimethylpropyl and phenyl radicals; R⁷ and R⁷′ independentlyrepresent methyl, ethyl, propyl and butyl radicals, or together with thecarbon atom to which they are attached form a cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl radical; R⁸ represents methylcarbonyl, phenyl,hydroxy, methoxy, cyano, methoxycarbonyl, ethoxycarbonyl,isopropoxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl, carboxyl,methoxycarbonyl, methylsulfonyl, methylthio, phenylsulfonyl, phenyl, 2-,3- or 4-pyridyl, 2-, 3- or 4-pyridyl N-oxide, N,N-dimethylamino,1-piperidinyl, 4-morpholinyl, 4-(N-methyl)piperazinyl and1-pyrrolidinyl.
 29. Compound of claim 26 wherein R⁴ and R⁵ together withthe nitrogen atom to which they are bonded form a pyrrolidinyl,piperidinyl, morpholinyl or piperazinyl radical.
 30. A pharmaceuticalcomposition comprising a compound of claim 26 and a pharmaceuticallyacceptable carrier.
 31. Method of inhibiting a retroviral proteasecomprising administering a protease inhibiting amount of a compositionof claim
 29. 32. Method of claim 30 wherein the retroviral protease isHIV protease.
 33. Method of treating a retroviral infection comprisingadministering an effective amount of a composition of claim
 29. 34.Method of claim 32 wherein the retroviral infection is an HIV infection.35. Method for treating AIDS comprising administering an effectiveamount of a composition of claim
 29. 36. A compound represented by theformula:

wherein: P¹ and P² independently represent hydrogen, alkoxycarbonyl,aralkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl,cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl, aralkanoyl,aroyl, aryloxycarbonyl, aryloxycarbonylalkyl, aryloxyalkanoyl,heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylalkanoyl,heterocyclylalkoxycarbonyl, heteroaralkanoyl, heteroaralkoxycarbonyl,heteroaryloxy-carbonyl, heteroaroyl, alkyl, alkenyl, cycloalkyl, aryl,aralkyl, aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl, aminocarbonyl,aminoalkanoyl, and mono- and disubstituted aminocarbonyl and mono- anddisubstituted aminoalkanoyl radicals wherein the substituents areselected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkyalkylradicals, or where said aminoalkanoyl radical is disubstituted, saidsubstituents along with the nitrogen atom to which they are attachedform a heterocycloalkyl or heteroaryl radical; R² represents alkyl,aryl, cycloalkyl, cycloalkylalkyl and aralkyl radicals, which radicalsare optionally substituted with a group selected from alkyl and halogenradicals, —NO₂, —C≡N, CF₃, —OR⁹, —SR⁹, wherein R⁹ represents hydrogenand alkyl radicals; R³ represents hydrogen, alkyl, haloalkyl, alkenyl,alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl,heteroaralkyl, aminoalkyl and mono- and disubstituted aminoalkylradicals, wherein said substituents are selected from alkyl, aryl,aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl,heterocycloalkyl, and heterocycloalkylalkyl radicals, or in the case ofa disubstituted aminoalkyl radical, said substituents along with thenitrogen atom to which they are attached, form a heterocycloalkyl or aheteroaryl radical, and thioalkyl, alkylthioalkyl and arylthioalkyl andthe sulfone and sulfoxide derivatives thereof; R⁴ represents hydrogenand radicals as defined by R³; R⁷ and R⁷′ independently representradicals as defined for R³; amino acid side chains selected from thegroup consisting of valine, isoleucine, glycine, alanine,allo-isoleucine, asparagine, leucine, glutamine, and t-butylglycine;radicals represented by the formulas —C(O)R¹⁶, —CO₂R¹⁶, —SO₂R¹⁶, —SR¹⁶,—CONR¹⁶R¹⁷, —CF₃ and —NR¹⁶R¹⁷; or R⁷ and R⁷′ together with the carbonatom to which they are attached form a cycloalkyl radical; R⁸ representscyano, hydroxyl, alkyl, alkoxy, cycloalkyl, aryl, aralkyl,heterocycloalkyl and heteroaryl radicals and radicals represented by theformulas C(O)R¹⁶, CO₂R¹⁶, SO₂R¹⁶, SR¹⁶, CONR¹⁶R¹⁷, CF₃ and NR¹⁶R¹⁷;wherein R¹⁶ and R¹⁷ independently represent hydrogen and radicals asdefined for R³, or R¹⁶ and R¹⁷ together with a nitrogen to which theyare attached in the formula NR¹⁶R¹⁷ represent heterocycloalkyl andheteroaryl radicals; n represents an integer of from 0 to
 6. 37. Apharmaceutical composition comprising a compound of claim 36 and apharmaceutically acceptable carrier.
 38. Method of inhibiting aretroviral protease comprising administering a protease inhibitingamount of a composition of claim
 37. 39. Method of claim 38 wherein theretroviral protease is HIV protease.
 40. Method of treating a retroviralinfection comprising administering an effective amount of a compositionof claim
 37. 41. Method of claim 39 wherein the retroviral infection isan HIV infection.
 42. Method for treating AIDS comprising administeringan effective amount of a composition of claim 37.